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Neupogen

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Overview

What is Neupogen?

Filgrastim is a human granulocyte colony-stimulating factor (G-CSF)‚ produced by recombinant DNA technology. NEUPOGEN is the Amgen Inc. trademark for Filgrastim‚ which has been selected as the name for recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF).

NEUPOGEN is a 175 amino acid protein manufactured by recombinant DNA technology. NEUPOGEN is produced by bacteria into which has been inserted the human granulocyte colony-stimulating factor gene. NEUPOGEN has a molecular weight of 18‚800 daltons. The protein has an amino acid sequence that is identical to the natural sequence predicted from human DNA sequence analysis‚ except for the addition of an N-terminal methionine necessary for expression in . Because NEUPOGEN is produced in the product is nonglycosylated and thus differs from G-CSF isolated from a human cell.

NEUPOGEN is a sterile‚ clear‚ colorless‚ preservative-free liquid for parenteral administration containing Filgrastim at a specific activity of 1.0 ± 0.6 x 10 U/mg (as measured by a cell mitogenesis assay). The product is available in single use vials and prefilled syringes. The single use vials contain either 300 mcg or 480 mcg Filgrastim at a fill volume of 1.0 mL or 1.6 mL, respectively. The single use prefilled syringes contain either 300 mcg or 480 mcg Filgrastim at a fill volume of 0.5 mL or 0.8 mL, respectively. See table below for product composition of each single use vial or prefilled syringe.



What does Neupogen look like?



What are the available doses of Neupogen?

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What should I talk to my health care provider before I take Neupogen?

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How should I use Neupogen?

NEUPOGEN is indicated to decrease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever (see ). A complete blood count (CBC) and platelet count should be obtained prior to chemotherapy‚ and twice per week (see ) during NEUPOGEN therapy to avoid leukocytosis and to monitor the neutrophil count. In phase 3 clinical studies‚ NEUPOGEN therapy was discontinued when the ANC was ≥ 10‚000/mm after the expected chemotherapy-induced nadir.

NEUPOGEN is indicated for reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of adults with AML.

NEUPOGEN is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae‚ eg‚ febrile neutropenia‚ in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by marrow transplantation (see ). It is recommended that CBCs and platelet counts be obtained at a minimum of 3 times per week (see ) following marrow infusion to monitor the recovery of marrow reconstitution.

NEUPOGEN is indicated for the mobilization of hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis. Mobilization allows for the collection of increased numbers of progenitor cells capable of engraftment compared with collection by leukapheresis without mobilization or bone marrow harvest. After myeloablative chemotherapy‚ the transplantation of an increased number of progenitor cells can lead to more rapid engraftment‚ which may result in a decreased need for supportive care (see ).

NEUPOGEN is indicated for chronic administration to reduce the incidence and duration of sequelae of neutropenia (eg‚ fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia (see ). It is essential that serial CBCs with differential and platelet counts‚ and an evaluation of bone marrow morphology and karyotype be performed prior to initiation of NEUPOGEN therapy (see ). The use of NEUPOGEN prior to confirmation of SCN may impair diagnostic efforts and may thus impair or delay evaluation and treatment of an underlying condition‚ other than SCN‚ causing the neutropenia.

NEUPOGEN is supplied in either vials or in prefilled syringes with UltraSafe Needle Guards. Following administration of NEUPOGEN from the prefilled syringe, the UltraSafe Needle Guard should be activated to prevent accidental needle sticks. To activate the UltraSafe Needle Guard, place your hands behind the needle, grasp the guard with one hand, and slide the guard forward until the needle is completely covered and the guard clicks into place. The prefilled syringe should be disposed of by placing the entire prefilled syringe with guard activated into an approved puncture-proof container.

The recommended starting dose of NEUPOGEN is 5 mcg/kg/day‚ administered as a single daily injection by SC bolus injection‚ by short IV infusion (15 to 30 minutes)‚ or by continuous SC or continuous IV infusion. A CBC and platelet count should be obtained before instituting NEUPOGEN therapy‚ and monitored twice weekly during therapy. Doses may be increased in increments of 5 mcg/kg for each chemotherapy cycle‚ according to the duration and severity of the ANC nadir.

NEUPOGEN should be administered no earlier than 24 hours after the administration of cytotoxic chemotherapy. NEUPOGEN should not be administered in the period 24 hours before the administration of chemotherapy (see ). NEUPOGEN should be administered daily for up to 2 weeks‚ until the ANC has reached 10‚000/mm following the expected chemotherapy-induced neutrophil nadir. The duration of NEUPOGEN therapy needed to attenuate chemotherapy-induced neutropenia may be dependent on the myelosuppressive potential of the chemotherapy regimen employed. NEUPOGEN therapy should be discontinued if the ANC surpasses 10‚000/mm after the expected chemotherapy-induced neutrophil nadir (see ). In phase 3 trials‚ efficacy was observed at doses of 4 to 8 mcg/kg/day.

The recommended dose of NEUPOGEN following BMT is 10 mcg/kg/day given as an IV infusion of 4 or 24 hours‚ or as a continuous 24-hour SC infusion. For patients receiving BMT‚ the first dose of NEUPOGEN should be administered at least 24 hours after cytotoxic chemotherapy and at least 24 hours after bone marrow infusion.

During the period of neutrophil recovery‚ the daily dose of NEUPOGEN should be titrated against the neutrophil response as follows:

*

The recommended dose of NEUPOGEN for the mobilization of PBPC is 10 mcg/kg/day SC‚ either as a bolus or a continuous infusion. It is recommended that NEUPOGEN be given for at least 4 days before the first leukapheresis procedure and continued until the last leukapheresis. Although the optimal duration of NEUPOGEN administration and leukapheresis schedule have not been established‚ administration of NEUPOGEN for 6 to 7 days with leukaphereses on days 5‚ 6‚ and 7 was found to be safe and effective (see for schedules used in clinical trials). Neutrophil counts should be monitored after 4 days of NEUPOGEN, and NEUPOGEN dose modification should be considered for those patients who develop a WBC count greater than  100‚000/mm.

In all clinical trials of NEUPOGEN for the mobilization of PBPC‚ NEUPOGEN was also administered after reinfusion of the collected cells (see ).

NEUPOGEN should be administered to those patients in whom a diagnosis of congenital‚ cyclic‚ or idiopathic neutropenia has been definitively confirmed. Other diseases associated with neutropenia should be ruled out.

Starting Dose:

Congenital Neutropenia: The recommended daily starting dose is 6 mcg/kg BID SC every day.

Idiopathic or Cyclic Neutropenia: The recommended daily starting dose is 5 mcg/kg as a single injection SC every day.

Dose Adjustments:

Chronic daily administration is required to maintain clinical benefit. Absolute neutrophil count should not be used as the sole indication of efficacy. The dose should be individually adjusted based on the patients’ clinical course as well as ANC. In the SCN postmarketing surveillance study, the reported median daily doses of NEUPOGENwere: 6.0 mcg/kg (congenital neutropenia), 2.1 mcg/kg (cyclic neutropenia), and 1.2 mcg/kg (idiopathic neutropenia). In rare instances, patients with congenital neutropenia have required doses of NEUPOGENgreater than or equal to 100 mcg/kg/day.

If required‚ NEUPOGEN may be diluted in 5% dextrose. NEUPOGEN diluted to concentrations between 5 and 15 mcg/mL should be protected from adsorption to plastic materials by the addition of Albumin (Human) to a final concentration of 2 mg/mL. When diluted in 5% dextrose or 5% dextrose plus Albumin (Human)‚ NEUPOGEN is compatible with glass bottles‚ PVC and polyolefin IV bags‚ and polypropylene syringes.

Dilution of NEUPOGEN to a final concentration of less than 5 mcg/mL is not recommended at any time.

NEUPOGEN should be stored in the refrigerator at 2° to 8°C (36° to 46°F). Avoid shaking. Prior to injection‚ NEUPOGEN may be allowed to reach room temperature for a maximum of 24 hours. Any vial or prefilled syringe left at room temperature for greater than 24 hours should be discarded. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration‚ whenever solution and container permit; if particulates or discoloration are observed‚ the container should not be used.

 


What interacts with Neupogen?

NEUPOGEN is contraindicated in patients with known hypersensitivity to -derived proteins‚ Filgrastim‚ or any component of the product.



What are the warnings of Neupogen?

The antianabolic action of the tetracyclines may cause an increase in BUN. While this is not a problem in those with normal renal function, in patients with significantly impaired renal function, higher serum levels of tetracycline may lead to azotemia, hyperphosphatemia and acidosis.

Allergic-type reactions occurring on initial or subsequent treatment have been reported in less than 1 in 4000 patients treated with NEUPOGEN. These have generally been characterized by systemic symptoms involving at least 2 body systems‚ most often skin (rash‚ urticaria‚ facial edema)‚ respiratory (wheezing‚ dyspnea)‚ and cardiovascular (hypotension‚ tachycardia). Some reactions occurred on initial exposure. Reactions tended to occur within the first 30 minutes after administration and appeared to occur more frequently in patients receiving NEUPOGEN IV. Rapid resolution of symptoms occurred in most cases after administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine. Symptoms recurred in more than half the patients who were rechallenged.

SPLENIC RUPTURE, INCLUDING FATAL CASES, HAS BEEN REPORTED FOLLOWING THE ADMINISTRATION OF NEUPOGEN. INDIVIDUALS RECEIVING NEUPOGEN WHO REPORT LEFT UPPER ABDOMINAL AND/OR SHOULDER TIP PAIN SHOULD BE EVALUATED FOR AN ENLARGED SPLEEN OR SPLENIC RUPTURE.

Acute respiratory distress syndrome (ARDS) has been reported in patients receiving NEUPOGEN, and is postulated to be secondary to an influx of neutrophils to sites of inflammation in the lungs. Patients receiving NEUPOGEN who develop fever, lung infiltrates, or respiratory distress should be evaluated for the possibility of ARDS. In the event that ARDS occurs, NEUPOGEN should be withheld until resolution of ARDS or discontinued. Patients should receive appropriate medical management for this condition.

Alveolar hemorrhage manifesting as pulmonary infiltrates and hemoptysis requiring hospitalization has been reported in healthy donors undergoing peripheral blood progenitor cell (PBPC) mobilization. Hemoptysis resolved with discontinuation of NEUPOGEN. The use of NEUPOGEN for PBPC mobilization in healthy donors is not an approved indication.

Severe sickle cell crises, in some cases resulting in death, have been associated with the use of NEUPOGEN in patients with sickle cell disorders. Only physicians qualified by specialized training or experience in the treatment of patients with sickle cell disorders should prescribe NEUPOGEN for such patients, and only after careful consideration of the potential risks and benefits.

The safety and efficacy of NEUPOGEN in the treatment of neutropenia due to other hematopoietic disorders (eg‚ myelodysplastic syndrome [MDS]) have not been established. Care should be taken to confirm the diagnosis of SCN before initiating NEUPOGEN therapy.

MDS and AML have been reported to occur in the natural history of congenital neutropenia without cytokine therapy. Cytogenetic abnormalities, transformation to MDS, and AML have also been observed in patients treated with NEUPOGEN for SCN. Based on available data including a postmarketing surveillance study, the risk of developing MDS and AML appears to be confined to the subset of patients with congenital neutropenia (see ). Abnormal cytogenetics and MDS have been associated with the eventual development of myeloid leukemia. The effect of NEUPOGEN on the development of abnormal cytogenetics and the effect of continued NEUPOGEN administration in patients with abnormal cytogenetics or MDS are unknown. If a patient with SCN develops abnormal cytogenetics or myelodysplasia‚ the risks and benefits of continuing NEUPOGEN should be carefully considered.


What are the precautions of Neupogen?

The safety and efficacy of NEUPOGEN given simultaneously with cytotoxic chemotherapy have not been established. Because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy‚ do not use NEUPOGEN in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy (see ).

The efficacy of NEUPOGEN has not been evaluated in patients receiving chemotherapy associated with delayed myelosuppression (eg, nitrosoureas) or with mitomycin C or with myelosuppressive doses of antimetabolites such as 5-fluorouracil.

The safety and efficacy of NEUPOGEN have not been evaluated in patients receiving concurrent radiation therapy. Simultaneous use of NEUPOGEN with chemotherapy and radiation therapy should be avoided.

NEUPOGEN is a growth factor that primarily stimulates neutrophils. However‚ the possibility that NEUPOGEN can act as a growth factor for any tumor type cannot be excluded. In a randomized study evaluating the effects of NEUPOGEN versus placebo in patients undergoing remission induction for AML, there was no significant difference in remission rate, disease-free, or overall survival (see ).

The safety of NEUPOGEN in chronic myeloid leukemia (CML) and myelodysplasia has not been established.

When NEUPOGEN is used to mobilize PBPC‚ tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. The effect of reinfusion of tumor cells has not been well studied‚ and the limited data available are inconclusive.

White blood cell counts of 100‚000/mm or greater were observed in approximately 2% of patients receiving NEUPOGEN at doses above 5 mcg/kg/day. There were no reports of adverse events associated with this degree of leukocytosis. In order to avoid the potential complications of excessive leukocytosis‚ a CBC is recommended twice per week during NEUPOGEN therapy (see ).

A transient increase in neutrophil counts is typically seen 1 to 2 days after initiation of NEUPOGEN therapy. However‚ for a sustained therapeutic response‚ NEUPOGEN therapy should be continued following chemotherapy until the post nadir ANC reaches 10‚000/mm. Therefore‚ the premature discontinuation of NEUPOGEN therapy‚ prior to the time of recovery from the expected neutrophil nadir‚ is generally not recommended (see ).

As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving NEUPOGEN has not been adequately determined. While available data suggest that a small proportion of patients developed binding antibodies to Filgrastim, the nature and specificity of these antibodies has not been adequately studied. In clinical studies comparing NEUPOGEN and Neulasta, the incidence of antibodies binding to NEUPOGEN was 3% (11/333). In these 11 patients, no evidence of a neutralizing response was observed using a cell-based bioassay. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors including timing of sampling, sample handling, concomitant medications, and underlying disease. Therefore, comparison of the incidence of antibodies to NEUPOGEN with the incidence of antibodies to other products may be misleading.

Cytopenias resulting from an antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors. There is a theoretical possibility that an antibody directed against Filgrastim may cross-react with endogenous G-CSF, resulting in immune-mediated neutropenia; however, this has not been reported in clinical studies or in post-marketing experience. Patients who develop hypersensitivity to Filgrastim (NEUPOGEN) may have allergic or hypersensitivity reactions to other -derived proteins.

Cutaneous vasculitis has been reported in patients treated with NEUPOGEN. In most cases‚ the severity of cutaneous vasculitis was moderate or severe. Most of the reports involved patients with SCN receiving long-term NEUPOGEN therapy. Symptoms of vasculitis generally developed simultaneously with an increase in the ANC and abated when the ANC decreased. Many patients were able to continue NEUPOGEN at a reduced dose.

Patients should be referred to the “Information for Patients and Caregivers” labeling included with the package insert in each dispensing pack of NEUPOGEN vials or NEUPOGEN prefilled syringes. The “Information for Patients and Caregivers” labeling provides information about neutrophils and neutropenia and the safety and efficacy of NEUPOGEN. It is not intended to be a disclosure of all known or possible effects.

A CBC and platelet count should be obtained prior to chemotherapy‚ and at regular intervals (twice per week) during NEUPOGEN therapy. Following cytotoxic chemotherapy‚ the neutrophil nadir occurred earlier during cycles when NEUPOGEN was administered‚ and WBC differentials demonstrated a left shift‚ including the appearance of promyelocytes and myeloblasts. In addition‚ the duration of severe neutropenia was reduced‚ and was followed by an accelerated recovery in the neutrophil counts.

Frequent CBCs and platelet counts are recommended (at least 3 times per week) following marrow transplantation.

During the initial 4 weeks of NEUPOGEN therapy and during the 2 weeks following any dose adjustment‚ a CBC with differential and platelet count should be performed twice weekly. Once a patient is clinically stable‚ a CBC with differential and platelet count should be performed monthly during the first year of treatment. Thereafter, if clinically stable, routine monitoring with regular CBCs (ie, as clinically indicated but at least quarterly) is recommended. Additionally, for those patients with congenital neutropenia, annual bone marrow and cytogenetic evaluations should be performed throughout the duration of treatment (see , ).

In clinical trials‚ the following laboratory results were observed:

Drug interactions between NEUPOGEN and other drugs have not been fully evaluated. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.

The carcinogenic potential of NEUPOGEN has not been studied. NEUPOGEN failed to induce bacterial gene mutations in either the presence or absence of a drug metabolizing enzyme system. NEUPOGEN had no observed effect on the fertility of male or female rats‚ or on gestation at doses up to 500 mcg/kg.

NEUPOGEN has been shown to have adverse effects in pregnant rabbits when given in doses 2 to 10 times the human dose. Since there are no adequate and well-controlled studies in pregnant women, the effect, if any, of NEUPOGEN on the developing fetus or the reproductive capacity of the mother is unknown. However, the scientific literature describes transplacental passage of NEUPOGEN when administered to pregnant rats during the latter part of gestation and apparent transplacental passage of NEUPOGEN when administered to pregnant humans by ≤ 30 hours prior to preterm delivery (≤ 30 weeks gestation). NEUPOGEN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In rabbits‚ increased abortion and embryolethality were observed in animals treated with NEUPOGEN at 80 mcg/kg/day. NEUPOGEN administered to pregnant rabbits at doses of 80 mcg/kg/day during the period of organogenesis was associated with increased fetal resorption‚ genitourinary bleeding‚ developmental abnormalities‚ decreased body weight‚ live births‚ and food consumption. External abnormalities were not observed in the fetuses of dams treated at 80 mcg/kg/day. Reproductive studies in pregnant rats have shown that NEUPOGEN was not associated with lethal‚ teratogenic‚ or behavioral effects on fetuses when administered by daily IV injection during the period of organogenesis at dose levels up to 575 mcg/kg/day.

In Segment III studies in rats‚ offspring of dams treated at > 20 mcg/kg/day exhibited a delay in external differentiation (detachment of auricles and descent of testes) and slight growth retardation‚ possibly due to lower body weight of females during rearing and nursing. Offspring of dams treated at 100 mcg/kg/day exhibited decreased body weights at birth‚ and a slightly reduced 4-day survival rate.

It is not known whether NEUPOGEN is excreted in human milk. Because many drugs are excreted in human milk‚ caution should be exercised if NEUPOGEN is administered to a nursing woman.

In a phase 3 study to assess the safety and efficacy of NEUPOGEN in the treatment of SCN, 120 patients with a median age of 12 years were studied. Of the 120 patients, 12 were infants (1 month to 2 years of age), 47 were children (2 to 12 years of age), and 9 were adolescents (12 to 16 years of age). Additional information is available from a SCN postmarketing surveillance study, which includes long-term follow-up of patients in the clinical studies and information from additional patients who entered directly into the postmarketing surveillance study. Of the 531 patients in the surveillance study as of 31 December 1997, 32 were infants, 200 were children, and 68 were adolescents (see , , , ).

Pediatric patients with congenital types of neutropenia (Kostmann’s syndrome, congenital agranulocytosis, or Schwachman-Diamond syndrome) have developed cytogenetic abnormalities and have undergone transformation to MDS and AML while receiving chronic NEUPOGEN treatment. The relationship of these events to NEUPOGEN administration is unknown (see , ).

Long-term follow-up data from the postmarketing surveillance study suggest that height and weight are not adversely affected in patients who received up to 5 years of NEUPOGEN treatment. Limited data from patients who were followed in the phase 3 study for 1.5 years did not suggest alterations in sexual maturation or endocrine function.

The safety and efficacy in neonates and patients with autoimmune neutropenia of infancy have not been established.

In the cancer setting‚ 12 pediatric patients with neuroblastoma have received up to 6 cycles of cyclophosphamide‚ cisplatin‚ doxorubicin‚ and etoposide chemotherapy concurrently with NEUPOGEN; in this population‚ NEUPOGEN was well tolerated. There was one report of palpable splenomegaly associated with NEUPOGEN therapy; however‚ the only consistently reported adverse event was musculoskeletal pain‚ which is no different from the experience in the adult population.

Among 855 subjects enrolled in 3 randomized, placebo-controlled trials of NEUPOGEN use following myelosuppressive chemotherapy, there were 232 subjects age 65 or older, and 22 subjects age 75 or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other clinical experience has not identified differences in the responses between elderly and younger patients.

Clinical studies of NEUPOGEN in other approved indications (ie, bone marrow transplant recipients, PBPC mobilization, and SCN) did not include sufficient numbers of subjects aged 65 and older to determine whether elderly subjects respond differently from younger subjects.

  • Cyclic fluctuations in the neutrophil counts were frequently observed in patients with congenital or idiopathic neutropenia after initiation of NEUPOGEN therapy.
  • Platelet counts were generally at the upper limits of normal prior to NEUPOGEN therapy. With NEUPOGEN therapy‚ platelet counts decreased but usually remained within normal limits (see ).
  • Early myeloid forms were noted in peripheral blood in most patients‚ including the appearance of metamyelocytes and myelocytes. Promyelocytes and myeloblasts were noted in some patients.
  • Relative increases were occasionally noted in the number of circulating eosinophils and basophils. No consistent increases were observed with NEUPOGEN therapy.
  • As in other trials‚ increases were observed in serum uric acid‚ lactic dehydrogenase‚ and serum alkaline phosphatase.



What are the side effects of Neupogen?

In clinical trials involving over 350 patients receiving NEUPOGEN following nonmyeloablative cytotoxic chemotherapy‚ most adverse experiences were the sequelae of the underlying malignancy or cytotoxic chemotherapy. In all phase 2 and 3 trials‚ medullary bone pain‚ reported in 24% of patients‚ was the only consistently observed adverse reaction attributed to NEUPOGEN therapy. This bone pain was generally reported to be of mild-to-moderate severity‚ and could be controlled in most patients with non-narcotic analgesics; infrequently‚ bone pain was severe enough to require narcotic analgesics. Bone pain was reported more frequently in patients treated with higher doses (20 to 100 mcg/kg/day) administered IV‚ and less frequently in patients treated with lower SC doses of NEUPOGEN (3 to 10 mcg/kg/day).

In the randomized‚ double-blind‚ placebo-controlled trial of NEUPOGEN therapy following combination chemotherapy in patients (n = 207) with small cell lung cancer‚ the following adverse events were reported during blinded cycles of study medication (placebo or NEUPOGEN at 4 to 8 mcg/kg/day). Events are reported as exposure-adjusted since patients remained on double-blind NEUPOGEN a median of 3 cycles versus 1 cycle for placebo.

In this study‚ there were no serious‚ life-threatening‚ or fatal adverse reactions attributed to NEUPOGEN therapy. Specifically‚ there were no reports of flu-like symptoms‚ pleuritis‚ pericarditis‚ or other major systemic reactions to NEUPOGEN.

Spontaneously reversible elevations in uric acid‚ lactate dehydrogenase‚ and alkaline phosphatase occurred in 27% to 58% of 98 patients receiving blinded NEUPOGEN therapy following cytotoxic chemotherapy; increases were generally mild-to-moderate. Transient decreases in blood pressure (less than 90/60 mmHg)‚ which did not require clinical treatment‚ were reported in 7 of 176 patients in phase 3 clinical studies following administration of NEUPOGEN. Cardiac events (myocardial infarctions‚ arrhythmias) have been reported in 11 of 375 cancer patients receiving NEUPOGEN in clinical studies; the relationship to NEUPOGEN therapy is unknown. No evidence of interaction of NEUPOGEN with other drugs was observed in the course of clinical trials (see ).

There has been no evidence for the development of antibodies or of a blunted or diminished response to NEUPOGEN in treated patients‚ including those receiving NEUPOGEN daily for almost 2 years.

In a randomized phase 3 clinical trial, 259 patients received NEUPOGEN and 262 patients received placebo postchemotherapy. Overall, the frequency of all reported adverse events was similar in both the NEUPOGEN and placebo groups (83% vs 82% in Induction 1; 61% vs 64% in Consolidation 1). Adverse events reported more frequently in the NEUPOGEN-treated group included: petechiae (17% vs 14%), epistaxis (9% vs 5%), and transfusion reactions (10% vs 5%). There were no significant differences in the frequency of these events.

There were a similar number of deaths in each treatment group during induction (25 NEUPOGEN vs 27 placebo). The primary causes of death included infection (9 vs 18), persistent leukemia (7 vs 5), and hemorrhage (6 vs 3). Of the hemorrhagic deaths, 5 cerebral hemorrhages were reported in the NEUPOGEN group and 1 in the placebo group. Other serious nonfatal hemorrhagic events were reported in the respiratory tract (4 vs 1), skin (4 vs 4), gastrointestinal tract (2 vs 2), urinary tract (1 vs 1), ocular (1 vs 0), and other nonspecific sites (2 vs 1). While 19 (7%) patients in the NEUPOGEN group and 5 (2%) patients in the placebo group experienced severe or fatal hemorrhagic events, overall, hemorrhagic adverse events were reported at a similar frequency in both groups (40% vs 38%). The time to transfusion-independent platelet recovery and the number of days of platelet transfusions were similar in both groups.

In clinical trials‚ the reported adverse effects were those typically seen in patients receiving intensive chemotherapy followed by bone marrow transplant (BMT). The most common events reported in both control and treatment groups included stomatitis, nausea, and vomiting‚ generally of mild-to-moderate severity and were considered unrelated to NEUPOGEN. In the randomized studies of BMT involving 167 patients who received study drug‚ the following events occurred more frequently in patients treated with Filgrastim than in controls: nausea (10% vs 4%)‚ vomiting (7% vs 3%)‚ hypertension (4% vs 0%)‚ rash (12% vs 10%)‚ and peritonitis (2% vs 0%). None of these events were reported by the investigator to be related to NEUPOGEN. One event of erythema nodosum was reported moderate in severity and possibly related to NEUPOGEN.

Generally‚ adverse events observed in nonrandomized studies were similar to those seen in randomized studies‚ occurred in a minority of patients, and were of mild-to-moderate severity. In one study (n = 45)‚ 3 serious adverse events reported by the investigator were considered possibly related to NEUPOGEN. These included 2 events of renal insufficiency and 1 event of capillary leak syndrome. The relationship of these events to NEUPOGEN remains unclear since they occurred in patients with culture-proven infection with clinical sepsis who were receiving potentially nephrotoxic antibacterial and antifungal therapy.

In clinical trials‚ 126 patients received NEUPOGEN for PBPC mobilization. In this setting‚ NEUPOGEN was generally well tolerated. Adverse events related to NEUPOGEN consisted primarily of mild-to-moderate musculoskeletal symptoms‚ reported in 44% of patients. These symptoms were predominantly events of medullary bone pain (33%). Headache was reported related to NEUPOGEN in 7% of patients. Transient increases in alkaline phosphatase related to NEUPOGEN were reported in 21% of the patients who had serum chemistries measured; most were mild-to-moderate.

All patients had increases in neutrophil counts during mobilization‚ consistent with the biological effects of NEUPOGEN. Two patients had a WBC count greater than 100‚000/mm. No sequelae were associated with any grade of leukocytosis.

Sixty-five percent of patients had mild-to-moderate anemia and 97% of patients had decreases in platelet counts; 5 patients (out of 126) had decreased platelet counts to less than 50‚000/mm. Anemia and thrombocytopenia have been reported to be related to leukapheresis; however‚ the possibility that NEUPOGEN mobilization may contribute to anemia or thrombocytopenia has not been ruled out.

Mild-to-moderate bone pain was reported in approximately 33% of patients in clinical trials. This symptom was readily controlled with non-narcotic analgesics. Generalized musculoskeletal pain was also noted in higher frequency in patients treated with NEUPOGEN. Palpable splenomegaly was observed in approximately 30% of patients. Abdominal or flank pain was seen infrequently, and thrombocytopenia (less than 50‚000/mm) was noted in 12% of patients with palpable spleens. Fewer than 3% of all patients underwent splenectomy‚ and most of these had a prestudy history of splenomegaly. Fewer than 6% of patients had thrombocytopenia (less than 50‚000/mm) during NEUPOGEN therapy‚ most of whom had a pre-existing history of thrombocytopenia. In most cases‚ thrombocytopenia was managed by NEUPOGEN dose reduction or interruption. An additional 5% of patients had platelet counts between 50‚000 and 100‚000/mm. There were no associated serious hemorrhagic sequelae in these patients. Epistaxis was noted in 15% of patients treated with NEUPOGEN but was associated with thrombocytopenia in 2% of patients. Anemia was reported in approximately 10% of patients‚ but in most cases appeared to be related to frequent diagnostic phlebotomy‚ chronic illness, or concomitant medications. Other adverse events infrequently observed and possibly related to NEUPOGEN therapy were: injection site reaction‚ rash‚ hepatomegaly‚ arthralgia‚ osteoporosis‚ cutaneous vasculitis‚ hematuria/proteinuria‚ alopecia‚ and exacerbation of some pre-existing skin disorders (eg‚ psoriasis).

Cytogenetic abnormalities, transformation to MDS, and AML have been observed in patients treated with NEUPOGEN for SCN (see , : ). As of 31 December 1997, data were available from a postmarketing surveillance study of 531 SCN patients with an average follow-up of 4.0 years. Based on analysis of these data, the risk of developing MDS and AML appears to be confined to the subset of patients with congenital neutropenia. A life-table analysis of these data revealed that the cumulative risk of developing leukemia or MDS by the end of the 8th year of NEUPOGEN treatment in a patient with congenital neutropenia was 16.5% (95% C.I. = 9.8%, 23.3%); this represents an annual rate of approximately 2%. Cytogenetic abnormalities, most commonly involving chromosome 7, have been reported in patients treated with NEUPOGEN who had previously documented normal cytogenetics. It is unknown whether the development of cytogenetic abnormalities, MDS, or AML is related to chronic daily NEUPOGEN administration or to the natural history of congenital neutropenia. It is also unknown if the rate of conversion in patients who have not received NEUPOGENis different from that of patients who have received NEUPOGEN. Routine monitoring through regular CBCs is recommended for all SCN patients. Additionally, annual bone marrow and cytogenetic evaluations are recommended in all patients with congenital neutropenia (see ).

The following adverse reactions have been identified during postapproval of NEUPOGEN. 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.

% of Blinded Cycles With Events
NEUPOGEN N = 384 Patient CyclesPlaceboN = 257 Patient Cycles
Event
Nausea/Vomiting5764
Skeletal Pain2211
Alopecia1827
Diarrhea1423
Neutropenic Fever1335
Mucositis1220
Fever1211
Fatigue1116
Anorexia911
Dyspnea911
Headache79
Cough68
Skin Rash69
Chest Pain56
Generalized Weakness47
Sore Throat49
Stomatitis510
Constipation510
Pain (Unspecified)27


  • splenic rupture (see : )
  • acute respiratory distress syndrome (ARDS) (see : )
  • alveolar hemorrhage and hemoptysis (see : )
  • sickle cell crisis (see : )
  • cutaneous vasculitis (see : )
  • Sweet’s syndrome (acute febrile neutrophilic dermatosis)



What should I look out for while using Neupogen?

NEUPOGEN is contraindicated in patients with known hypersensitivity to -derived proteins‚ Filgrastim‚ or any component of the product.

Allergic-type reactions occurring on initial or subsequent treatment have been reported in less than 1 in 4000 patients treated with NEUPOGEN. These have generally been characterized by systemic symptoms involving at least 2 body systems‚ most often skin (rash‚ urticaria‚ facial edema)‚ respiratory (wheezing‚ dyspnea)‚ and cardiovascular (hypotension‚ tachycardia). Some reactions occurred on initial exposure. Reactions tended to occur within the first 30 minutes after administration and appeared to occur more frequently in patients receiving NEUPOGEN IV. Rapid resolution of symptoms occurred in most cases after administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine. Symptoms recurred in more than half the patients who were rechallenged.

SPLENIC RUPTURE, INCLUDING FATAL CASES, HAS BEEN REPORTED FOLLOWING THE ADMINISTRATION OF NEUPOGEN. INDIVIDUALS RECEIVING NEUPOGEN WHO REPORT LEFT UPPER ABDOMINAL AND/OR SHOULDER TIP PAIN SHOULD BE EVALUATED FOR AN ENLARGED SPLEEN OR SPLENIC RUPTURE.

Acute respiratory distress syndrome (ARDS) has been reported in patients receiving NEUPOGEN, and is postulated to be secondary to an influx of neutrophils to sites of inflammation in the lungs. Patients receiving NEUPOGEN who develop fever, lung infiltrates, or respiratory distress should be evaluated for the possibility of ARDS. In the event that ARDS occurs, NEUPOGEN should be withheld until resolution of ARDS or discontinued. Patients should receive appropriate medical management for this condition.

Alveolar hemorrhage manifesting as pulmonary infiltrates and hemoptysis requiring hospitalization has been reported in healthy donors undergoing peripheral blood progenitor cell (PBPC) mobilization. Hemoptysis resolved with discontinuation of NEUPOGEN. The use of NEUPOGEN for PBPC mobilization in healthy donors is not an approved indication.

Severe sickle cell crises, in some cases resulting in death, have been associated with the use of NEUPOGEN in patients with sickle cell disorders. Only physicians qualified by specialized training or experience in the treatment of patients with sickle cell disorders should prescribe NEUPOGEN for such patients, and only after careful consideration of the potential risks and benefits.

The safety and efficacy of NEUPOGEN in the treatment of neutropenia due to other hematopoietic disorders (eg‚ myelodysplastic syndrome [MDS]) have not been established. Care should be taken to confirm the diagnosis of SCN before initiating NEUPOGEN therapy.

MDS and AML have been reported to occur in the natural history of congenital neutropenia without cytokine therapy. Cytogenetic abnormalities, transformation to MDS, and AML have also been observed in patients treated with NEUPOGEN for SCN. Based on available data including a postmarketing surveillance study, the risk of developing MDS and AML appears to be confined to the subset of patients with congenital neutropenia (see ). Abnormal cytogenetics and MDS have been associated with the eventual development of myeloid leukemia. The effect of NEUPOGEN on the development of abnormal cytogenetics and the effect of continued NEUPOGEN administration in patients with abnormal cytogenetics or MDS are unknown. If a patient with SCN develops abnormal cytogenetics or myelodysplasia‚ the risks and benefits of continuing NEUPOGEN should be carefully considered.


What might happen if I take too much Neupogen?

In cancer patients receiving NEUPOGEN as an adjunct to myelosuppressive chemotherapy‚ it is recommended‚ to avoid the potential risks of excessive leukocytosis‚ that NEUPOGEN therapy be discontinued if the ANC surpasses 10‚000/mm after the chemotherapy-induced ANC nadir has occurred. Doses of NEUPOGEN that increase the ANC beyond 10‚000/mm may not result in any additional clinical benefit.

The maximum tolerated dose of NEUPOGEN has not been determined. Efficacy was demonstrated at doses of 4 to 8 mcg/kg/day in the phase 3 study of nonmyeloablative chemotherapy. Patients in the BMT studies received up to 138 mcg/kg/day without toxic effects‚ although there was a flattening of the dose response curve above daily doses of greater than 10 mcg/kg/day.

In NEUPOGEN clinical trials of cancer patients receiving myelosuppressive chemotherapy‚ WBC counts > 100‚000/mm have been reported in less than 5% of patients‚ but were not associated with any reported adverse clinical effects.

In cancer patients receiving myelosuppressive chemotherapy‚ discontinuation of NEUPOGEN therapy usually results in a 50% decrease in circulating neutrophils within 1 to 2 days‚ with a return to pretreatment levels in 1 to 7 days.


How should I store and handle Neupogen?

Store bottles of 1000 SINGULAIR 5-mg chewable tablets and 8000 SINGULAIR 10-mg film-coated tablets at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from moisture and light. Store in original container. When product container is subdivided, repackage into a well-closed, light resistant container. NEUPOGEN: Use only one dose per vial; do not re-enter the vial. Discard unused portions. Do not save unused drug for later administration.Use only one dose per prefilled syringe. Discard unused portions. Do not save unused drug for later administration.Single-dose‚ preservative-free vials containing 300 mcg (1 mL) of Filgrastim (300 mcg/mL). 1 Vial ();  Dispensing packs of 10 (). Single-dose‚ preservative-free, prefilled syringes with 27 gauge, ½ inch needles with an UltraSafe Needle Guard, containing 300 mcg (0.5 mL) of Filgrastim (600 mcg/mL). Dispensing packs of 10 (). Single-dose‚ preservative-free, prefilled syringes with 27 gauge, ½ inch needles with an UltraSafe Needle Guard, containing 480 mcg (0.8 mL) of Filgrastim (600 mcg/mL). Dispensing packs of 10 ().The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex).NEUPOGEN should be stored at 2° to 8°C (36° to 46°F). Avoid shaking.NEUPOGEN: Use only one dose per vial; do not re-enter the vial. Discard unused portions. Do not save unused drug for later administration.Use only one dose per prefilled syringe. Discard unused portions. Do not save unused drug for later administration.Single-dose‚ preservative-free vials containing 300 mcg (1 mL) of Filgrastim (300 mcg/mL). 1 Vial ();  Dispensing packs of 10 (). Single-dose‚ preservative-free, prefilled syringes with 27 gauge, ½ inch needles with an UltraSafe Needle Guard, containing 300 mcg (0.5 mL) of Filgrastim (600 mcg/mL). Dispensing packs of 10 (). Single-dose‚ preservative-free, prefilled syringes with 27 gauge, ½ inch needles with an UltraSafe Needle Guard, containing 480 mcg (0.8 mL) of Filgrastim (600 mcg/mL). Dispensing packs of 10 ().The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex).NEUPOGEN should be stored at 2° to 8°C (36° to 46°F). Avoid shaking.NEUPOGEN: Use only one dose per vial; do not re-enter the vial. Discard unused portions. Do not save unused drug for later administration.Use only one dose per prefilled syringe. Discard unused portions. Do not save unused drug for later administration.Single-dose‚ preservative-free vials containing 300 mcg (1 mL) of Filgrastim (300 mcg/mL). 1 Vial ();  Dispensing packs of 10 (). Single-dose‚ preservative-free, prefilled syringes with 27 gauge, ½ inch needles with an UltraSafe Needle Guard, containing 300 mcg (0.5 mL) of Filgrastim (600 mcg/mL). Dispensing packs of 10 (). Single-dose‚ preservative-free, prefilled syringes with 27 gauge, ½ inch needles with an UltraSafe Needle Guard, containing 480 mcg (0.8 mL) of Filgrastim (600 mcg/mL). Dispensing packs of 10 ().The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex).NEUPOGEN should be stored at 2° to 8°C (36° to 46°F). Avoid shaking.NEUPOGEN: Use only one dose per vial; do not re-enter the vial. Discard unused portions. Do not save unused drug for later administration.Use only one dose per prefilled syringe. Discard unused portions. Do not save unused drug for later administration.Single-dose‚ preservative-free vials containing 300 mcg (1 mL) of Filgrastim (300 mcg/mL). 1 Vial ();  Dispensing packs of 10 (). Single-dose‚ preservative-free, prefilled syringes with 27 gauge, ½ inch needles with an UltraSafe Needle Guard, containing 300 mcg (0.5 mL) of Filgrastim (600 mcg/mL). Dispensing packs of 10 (). Single-dose‚ preservative-free, prefilled syringes with 27 gauge, ½ inch needles with an UltraSafe Needle Guard, containing 480 mcg (0.8 mL) of Filgrastim (600 mcg/mL). Dispensing packs of 10 ().The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex).NEUPOGEN should be stored at 2° to 8°C (36° to 46°F). Avoid shaking.NEUPOGEN: Use only one dose per vial; do not re-enter the vial. Discard unused portions. Do not save unused drug for later administration.Use only one dose per prefilled syringe. Discard unused portions. Do not save unused drug for later administration.Single-dose‚ preservative-free vials containing 300 mcg (1 mL) of Filgrastim (300 mcg/mL). 1 Vial ();  Dispensing packs of 10 (). Single-dose‚ preservative-free, prefilled syringes with 27 gauge, ½ inch needles with an UltraSafe Needle Guard, containing 300 mcg (0.5 mL) of Filgrastim (600 mcg/mL). Dispensing packs of 10 (). Single-dose‚ preservative-free, prefilled syringes with 27 gauge, ½ inch needles with an UltraSafe Needle Guard, containing 480 mcg (0.8 mL) of Filgrastim (600 mcg/mL). Dispensing packs of 10 ().The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex).NEUPOGEN should be stored at 2° to 8°C (36° to 46°F). Avoid shaking.NEUPOGEN: Use only one dose per vial; do not re-enter the vial. Discard unused portions. Do not save unused drug for later administration.Use only one dose per prefilled syringe. Discard unused portions. Do not save unused drug for later administration.Single-dose‚ preservative-free vials containing 300 mcg (1 mL) of Filgrastim (300 mcg/mL). 1 Vial ();  Dispensing packs of 10 (). Single-dose‚ preservative-free, prefilled syringes with 27 gauge, ½ inch needles with an UltraSafe Needle Guard, containing 300 mcg (0.5 mL) of Filgrastim (600 mcg/mL). Dispensing packs of 10 (). Single-dose‚ preservative-free, prefilled syringes with 27 gauge, ½ inch needles with an UltraSafe Needle Guard, containing 480 mcg (0.8 mL) of Filgrastim (600 mcg/mL). Dispensing packs of 10 ().The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex).NEUPOGEN should be stored at 2° to 8°C (36° to 46°F). Avoid shaking.NEUPOGEN: Use only one dose per vial; do not re-enter the vial. Discard unused portions. Do not save unused drug for later administration.Use only one dose per prefilled syringe. Discard unused portions. Do not save unused drug for later administration.Single-dose‚ preservative-free vials containing 300 mcg (1 mL) of Filgrastim (300 mcg/mL). 1 Vial ();  Dispensing packs of 10 (). Single-dose‚ preservative-free, prefilled syringes with 27 gauge, ½ inch needles with an UltraSafe Needle Guard, containing 300 mcg (0.5 mL) of Filgrastim (600 mcg/mL). Dispensing packs of 10 (). Single-dose‚ preservative-free, prefilled syringes with 27 gauge, ½ inch needles with an UltraSafe Needle Guard, containing 480 mcg (0.8 mL) of Filgrastim (600 mcg/mL). Dispensing packs of 10 ().The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex).NEUPOGEN should be stored at 2° to 8°C (36° to 46°F). Avoid shaking.


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Clinical Information

Chemical Structure

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Clinical Pharmacology

Colony-stimulating factors are glycoproteins which act on hematopoietic cells by binding to specific cell surface receptors and stimulating proliferation‚ differentiation commitment‚ and some end-cell functional activation.

Endogenous G-CSF is a lineage specific colony-stimulating factor which is produced by monocytes‚ fibroblasts, and endothelial cells. G-CSF regulates the production of neutrophils within the bone marrow and affects neutrophil progenitor proliferation‚ differentiation, and selected end-cell functional activation (including enhanced phagocytic ability‚ priming of the cellular metabolism associated with respiratory burst‚ antibody dependent killing,and the increased expression of some functions associated with cell surface antigens). G-CSF is not species specific and has been shown to have minimal direct in vivo or in vitro effects on the production of hematopoietic cell types other than the neutrophil lineage.

Filgrastim was administered to monkeys‚ dogs‚ hamsters‚ rats‚ and mice as part of a preclinical toxicology program which included single-dose acute‚ repeated-dose subacute‚ subchronic‚ and chronic studies. Single-dose administration of Filgrastim by the oral‚ intravenous (IV)‚ subcutaneous (SC)‚ or intraperitoneal (IP) routes resulted in no significant toxicity in mice‚ rats‚ hamsters‚ or monkeys. Although no deaths were observed in mice‚ rats‚ or monkeys at dose levels up to 3450 mcg/kg or in hamsters using single doses up to approximately 860 mcg/kg‚ deaths were observed in a subchronic (13-week) study in monkeys. In this study‚ evidence of neurological symptoms was seen in monkeys treated with doses of Filgrastim greater than 1150 mcg/kg/day for up to 18 days. Deaths were seen in 5 of the 8 treated animals and were associated with 15- to 28-fold increases in peripheral leukocyte counts‚ and neutrophil-infiltrated hemorrhagic foci were seen in both the cerebrum and cerebellum. In contrast‚ no monkeys died following 13 weeks of daily IV administration of Filgrastim at a dose level of 115 mcg/kg. In an ensuing 52-week study‚ one 115 mcg/kg dosed female monkey died after 18 weeks of daily IV administration of Filgrastim. Death was attributed to cardiopulmonary insufficiency.

In subacute‚ repeated-dose studies‚ changes observed were attributable to the expected pharmacological actions of Filgrastim (ie‚ dose-dependent increases in white cell counts‚ increased circulating segmented neutrophils‚ and increased myeloid:erythroid ratio in bone marrow). In all species‚ histopathologic examination of the liver and spleen revealed evidence of ongoing extramedullary granulopoiesis; increased spleen weights were seen in all species and appeared to be dose-related. A dose-dependent increase in serum alkaline phosphatase was observed in rats‚ and may reflect increased activity of osteoblasts and osteoclasts. Changes in serum chemistry values were reversible following discontinuation of treatment.

In rats treated at doses of 1150 mcg/kg/day for 4 weeks (5 of 32 animals) and for 13 weeks at doses of 100 mcg/kg/day (4 of 32 animals) and 500 mcg/kg/day (6 of 32 animals)‚ articular swelling of the hind legs was observed. Some degree of hind leg dysfunction was also observed; however‚ symptoms reversed following cessation of dosing. In rats‚ osteoclasis and osteoanagenesis were found in the femur‚ humerus‚ coccyx‚ and hind legs (where they were accompanied by synovitis) after IV treatment for 4 weeks (115 to 1150 mcg/kg/day)‚ and in the sternum after IV treatment for 13 weeks (115 to 575 mcg/kg/day). These effects reversed to normal within 4 to 5 weeks following cessation of treatment.

In the 52-week chronic‚ repeated-dose studies performed in rats (IP injection up to 57.5 mcg/kg/day)‚ and cynomolgus monkeys (IV injection of up to 115 mcg/kg/day)‚ changes observed were similar to those noted in the subacute studies. Expected pharmacological actions of Filgrastim included dose-dependent increases in white cell counts‚ increased circulating segmented neutrophils and alkaline phosphatase levels‚ and increased myeloid:erythroid ratios in the bone marrow. Decreases in platelet counts were also noted in primates. In no animals tested were hemorrhagic complications observed. Rats displayed dose-related swelling of the hind limb‚ accompanied by some degree of hind limb dysfunction; osteopathy was noted microscopically. Enlarged spleens (both species) and livers (monkeys)‚ reflective of ongoing extramedullary granulopoiesis‚ as well as myeloid hyperplasia of the bone marrow‚ were observed in a dose-dependent manner.

In phase 1 studies involving 96 patients with various nonmyeloid malignancies‚ NEUPOGEN administration resulted in a dose-dependent increase in circulating neutrophil counts over the dose range of 1 to 70 mcg/kg/day. This increase in neutrophil counts was observed whether NEUPOGEN was administered IV (1 to 70 mcg/kg twice daily)‚ SC (1 to 3 mcg/kg once daily)‚or by continuous SC infusion (3 to 11 mcg/kg/day). With discontinuation of NEUPOGEN therapy‚ neutrophil counts returned to baseline‚ in most cases within 4 days. Isolated neutrophils displayed normal phagocytic (measured by zymosan-stimulated chemoluminescence) and chemotactic (measured by migration under agarose using N-formyl-methionyl-leucyl-phenylalanine [fMLP] as the chemotaxin) activity in vitro.

The absolute monocyte count was reported to increase in a dose-dependent manner in most patients receiving NEUPOGEN; however‚ the percentage of monocytes in the differential count remained within the normal range. In all studies to date‚ absolute counts of both eosinophils and basophils did not change and were within the normal range following administration of NEUPOGEN. Increases in lymphocyte counts following NEUPOGEN administration have been reported in some normal subjects and cancer patients.

White blood cell (WBC) differentials obtained during clinical trials have demonstrated a shift towards earlier granulocyte progenitor cells (left shift)‚ including the appearance of promyelocytes and myeloblasts‚ usually during neutrophil recovery following the chemotherapy-induced nadir. In addition‚ Dohle bodies‚ increased granulocyte granulation‚ and hypersegmented neutrophils have been observed. Such changes were transient and were not associated with clinical sequelae, nor were they necessarily associated with infection.

Absorption and clearance of NEUPOGEN follows first-order pharmacokinetic modeling without apparent concentration dependence. A positive linear correlation occurred between the parenteral dose and both the serum concentration and area under the concentration-time curves. Continuous IV infusion of 20 mcg/kg of NEUPOGEN over 24 hours resulted in mean and median serum concentrations of approximately 48 and 56 ng/mL‚ respectively. Subcutaneous administration of 3.45 mcg/kg and 11.5 mcg/kg resulted in maximum serum concentrations of 4 and 49 ng/mL‚ respectively‚ within 2 to 8 hours. The volume of distribution averaged 150 mL/kg in both normal subjects and cancer patients. The elimination half-life‚ in both normal subjects and cancer patients‚ was approximately 3.5 hours. Clearance rates of NEUPOGEN were approximately 0.5 to 0.7 mL/minute/kg. Single parenteral doses or daily IV doses‚ over a 14-day period‚ resulted in comparable half-lives. The half-lives were similar for IV administration (231 minutes‚ following doses of 34.5 mcg/kg) and for SC administration (210 minutes‚ following NEUPOGEN doses of 3.45 mcg/kg). Continuous 24-hour IV infusions of 20 mcg/kg over an 11- to 20-day period produced steady-state serum concentrations of NEUPOGEN with no evidence of drug accumulation over the time period investigated.

Pharmacokinetic data in geriatric patients (≥ 65 years) are not available.

Non-Clinical Toxicology
NEUPOGEN is contraindicated in patients with known hypersensitivity to -derived proteins‚ Filgrastim‚ or any component of the product.

Allergic-type reactions occurring on initial or subsequent treatment have been reported in less than 1 in 4000 patients treated with NEUPOGEN. These have generally been characterized by systemic symptoms involving at least 2 body systems‚ most often skin (rash‚ urticaria‚ facial edema)‚ respiratory (wheezing‚ dyspnea)‚ and cardiovascular (hypotension‚ tachycardia). Some reactions occurred on initial exposure. Reactions tended to occur within the first 30 minutes after administration and appeared to occur more frequently in patients receiving NEUPOGEN IV. Rapid resolution of symptoms occurred in most cases after administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine. Symptoms recurred in more than half the patients who were rechallenged.

SPLENIC RUPTURE, INCLUDING FATAL CASES, HAS BEEN REPORTED FOLLOWING THE ADMINISTRATION OF NEUPOGEN. INDIVIDUALS RECEIVING NEUPOGEN WHO REPORT LEFT UPPER ABDOMINAL AND/OR SHOULDER TIP PAIN SHOULD BE EVALUATED FOR AN ENLARGED SPLEEN OR SPLENIC RUPTURE.

Acute respiratory distress syndrome (ARDS) has been reported in patients receiving NEUPOGEN, and is postulated to be secondary to an influx of neutrophils to sites of inflammation in the lungs. Patients receiving NEUPOGEN who develop fever, lung infiltrates, or respiratory distress should be evaluated for the possibility of ARDS. In the event that ARDS occurs, NEUPOGEN should be withheld until resolution of ARDS or discontinued. Patients should receive appropriate medical management for this condition.

Alveolar hemorrhage manifesting as pulmonary infiltrates and hemoptysis requiring hospitalization has been reported in healthy donors undergoing peripheral blood progenitor cell (PBPC) mobilization. Hemoptysis resolved with discontinuation of NEUPOGEN. The use of NEUPOGEN for PBPC mobilization in healthy donors is not an approved indication.

Severe sickle cell crises, in some cases resulting in death, have been associated with the use of NEUPOGEN in patients with sickle cell disorders. Only physicians qualified by specialized training or experience in the treatment of patients with sickle cell disorders should prescribe NEUPOGEN for such patients, and only after careful consideration of the potential risks and benefits.

The safety and efficacy of NEUPOGEN in the treatment of neutropenia due to other hematopoietic disorders (eg‚ myelodysplastic syndrome [MDS]) have not been established. Care should be taken to confirm the diagnosis of SCN before initiating NEUPOGEN therapy.

MDS and AML have been reported to occur in the natural history of congenital neutropenia without cytokine therapy. Cytogenetic abnormalities, transformation to MDS, and AML have also been observed in patients treated with NEUPOGEN for SCN. Based on available data including a postmarketing surveillance study, the risk of developing MDS and AML appears to be confined to the subset of patients with congenital neutropenia (see ). Abnormal cytogenetics and MDS have been associated with the eventual development of myeloid leukemia. The effect of NEUPOGEN on the development of abnormal cytogenetics and the effect of continued NEUPOGEN administration in patients with abnormal cytogenetics or MDS are unknown. If a patient with SCN develops abnormal cytogenetics or myelodysplasia‚ the risks and benefits of continuing NEUPOGEN should be carefully considered.

The safety and efficacy of NEUPOGEN given simultaneously with cytotoxic chemotherapy have not been established. Because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy‚ do not use NEUPOGEN in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy (see ).

The efficacy of NEUPOGEN has not been evaluated in patients receiving chemotherapy associated with delayed myelosuppression (eg, nitrosoureas) or with mitomycin C or with myelosuppressive doses of antimetabolites such as 5-fluorouracil.

The safety and efficacy of NEUPOGEN have not been evaluated in patients receiving concurrent radiation therapy. Simultaneous use of NEUPOGEN with chemotherapy and radiation therapy should be avoided.

NEUPOGEN is a growth factor that primarily stimulates neutrophils. However‚ the possibility that NEUPOGEN can act as a growth factor for any tumor type cannot be excluded. In a randomized study evaluating the effects of NEUPOGEN versus placebo in patients undergoing remission induction for AML, there was no significant difference in remission rate, disease-free, or overall survival (see ).

The safety of NEUPOGEN in chronic myeloid leukemia (CML) and myelodysplasia has not been established.

When NEUPOGEN is used to mobilize PBPC‚ tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. The effect of reinfusion of tumor cells has not been well studied‚ and the limited data available are inconclusive.

White blood cell counts of 100‚000/mm or greater were observed in approximately 2% of patients receiving NEUPOGEN at doses above 5 mcg/kg/day. There were no reports of adverse events associated with this degree of leukocytosis. In order to avoid the potential complications of excessive leukocytosis‚ a CBC is recommended twice per week during NEUPOGEN therapy (see ).

A transient increase in neutrophil counts is typically seen 1 to 2 days after initiation of NEUPOGEN therapy. However‚ for a sustained therapeutic response‚ NEUPOGEN therapy should be continued following chemotherapy until the post nadir ANC reaches 10‚000/mm. Therefore‚ the premature discontinuation of NEUPOGEN therapy‚ prior to the time of recovery from the expected neutrophil nadir‚ is generally not recommended (see ).

As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving NEUPOGEN has not been adequately determined. While available data suggest that a small proportion of patients developed binding antibodies to Filgrastim, the nature and specificity of these antibodies has not been adequately studied. In clinical studies comparing NEUPOGEN and Neulasta, the incidence of antibodies binding to NEUPOGEN was 3% (11/333). In these 11 patients, no evidence of a neutralizing response was observed using a cell-based bioassay. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors including timing of sampling, sample handling, concomitant medications, and underlying disease. Therefore, comparison of the incidence of antibodies to NEUPOGEN with the incidence of antibodies to other products may be misleading.

Cytopenias resulting from an antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors. There is a theoretical possibility that an antibody directed against Filgrastim may cross-react with endogenous G-CSF, resulting in immune-mediated neutropenia; however, this has not been reported in clinical studies or in post-marketing experience. Patients who develop hypersensitivity to Filgrastim (NEUPOGEN) may have allergic or hypersensitivity reactions to other -derived proteins.

Cutaneous vasculitis has been reported in patients treated with NEUPOGEN. In most cases‚ the severity of cutaneous vasculitis was moderate or severe. Most of the reports involved patients with SCN receiving long-term NEUPOGEN therapy. Symptoms of vasculitis generally developed simultaneously with an increase in the ANC and abated when the ANC decreased. Many patients were able to continue NEUPOGEN at a reduced dose.

Patients should be referred to the “Information for Patients and Caregivers” labeling included with the package insert in each dispensing pack of NEUPOGEN vials or NEUPOGEN prefilled syringes. The “Information for Patients and Caregivers” labeling provides information about neutrophils and neutropenia and the safety and efficacy of NEUPOGEN. It is not intended to be a disclosure of all known or possible effects.

A CBC and platelet count should be obtained prior to chemotherapy‚ and at regular intervals (twice per week) during NEUPOGEN therapy. Following cytotoxic chemotherapy‚ the neutrophil nadir occurred earlier during cycles when NEUPOGEN was administered‚ and WBC differentials demonstrated a left shift‚ including the appearance of promyelocytes and myeloblasts. In addition‚ the duration of severe neutropenia was reduced‚ and was followed by an accelerated recovery in the neutrophil counts.

Frequent CBCs and platelet counts are recommended (at least 3 times per week) following marrow transplantation.

During the initial 4 weeks of NEUPOGEN therapy and during the 2 weeks following any dose adjustment‚ a CBC with differential and platelet count should be performed twice weekly. Once a patient is clinically stable‚ a CBC with differential and platelet count should be performed monthly during the first year of treatment. Thereafter, if clinically stable, routine monitoring with regular CBCs (ie, as clinically indicated but at least quarterly) is recommended. Additionally, for those patients with congenital neutropenia, annual bone marrow and cytogenetic evaluations should be performed throughout the duration of treatment (see , ).

In clinical trials‚ the following laboratory results were observed:

Drug interactions between NEUPOGEN and other drugs have not been fully evaluated. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.

The carcinogenic potential of NEUPOGEN has not been studied. NEUPOGEN failed to induce bacterial gene mutations in either the presence or absence of a drug metabolizing enzyme system. NEUPOGEN had no observed effect on the fertility of male or female rats‚ or on gestation at doses up to 500 mcg/kg.

NEUPOGEN has been shown to have adverse effects in pregnant rabbits when given in doses 2 to 10 times the human dose. Since there are no adequate and well-controlled studies in pregnant women, the effect, if any, of NEUPOGEN on the developing fetus or the reproductive capacity of the mother is unknown. However, the scientific literature describes transplacental passage of NEUPOGEN when administered to pregnant rats during the latter part of gestation and apparent transplacental passage of NEUPOGEN when administered to pregnant humans by ≤ 30 hours prior to preterm delivery (≤ 30 weeks gestation). NEUPOGEN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In rabbits‚ increased abortion and embryolethality were observed in animals treated with NEUPOGEN at 80 mcg/kg/day. NEUPOGEN administered to pregnant rabbits at doses of 80 mcg/kg/day during the period of organogenesis was associated with increased fetal resorption‚ genitourinary bleeding‚ developmental abnormalities‚ decreased body weight‚ live births‚ and food consumption. External abnormalities were not observed in the fetuses of dams treated at 80 mcg/kg/day. Reproductive studies in pregnant rats have shown that NEUPOGEN was not associated with lethal‚ teratogenic‚ or behavioral effects on fetuses when administered by daily IV injection during the period of organogenesis at dose levels up to 575 mcg/kg/day.

In Segment III studies in rats‚ offspring of dams treated at > 20 mcg/kg/day exhibited a delay in external differentiation (detachment of auricles and descent of testes) and slight growth retardation‚ possibly due to lower body weight of females during rearing and nursing. Offspring of dams treated at 100 mcg/kg/day exhibited decreased body weights at birth‚ and a slightly reduced 4-day survival rate.

It is not known whether NEUPOGEN is excreted in human milk. Because many drugs are excreted in human milk‚ caution should be exercised if NEUPOGEN is administered to a nursing woman.

In a phase 3 study to assess the safety and efficacy of NEUPOGEN in the treatment of SCN, 120 patients with a median age of 12 years were studied. Of the 120 patients, 12 were infants (1 month to 2 years of age), 47 were children (2 to 12 years of age), and 9 were adolescents (12 to 16 years of age). Additional information is available from a SCN postmarketing surveillance study, which includes long-term follow-up of patients in the clinical studies and information from additional patients who entered directly into the postmarketing surveillance study. Of the 531 patients in the surveillance study as of 31 December 1997, 32 were infants, 200 were children, and 68 were adolescents (see , , , ).

Pediatric patients with congenital types of neutropenia (Kostmann’s syndrome, congenital agranulocytosis, or Schwachman-Diamond syndrome) have developed cytogenetic abnormalities and have undergone transformation to MDS and AML while receiving chronic NEUPOGEN treatment. The relationship of these events to NEUPOGEN administration is unknown (see , ).

Long-term follow-up data from the postmarketing surveillance study suggest that height and weight are not adversely affected in patients who received up to 5 years of NEUPOGEN treatment. Limited data from patients who were followed in the phase 3 study for 1.5 years did not suggest alterations in sexual maturation or endocrine function.

The safety and efficacy in neonates and patients with autoimmune neutropenia of infancy have not been established.

In the cancer setting‚ 12 pediatric patients with neuroblastoma have received up to 6 cycles of cyclophosphamide‚ cisplatin‚ doxorubicin‚ and etoposide chemotherapy concurrently with NEUPOGEN; in this population‚ NEUPOGEN was well tolerated. There was one report of palpable splenomegaly associated with NEUPOGEN therapy; however‚ the only consistently reported adverse event was musculoskeletal pain‚ which is no different from the experience in the adult population.

Among 855 subjects enrolled in 3 randomized, placebo-controlled trials of NEUPOGEN use following myelosuppressive chemotherapy, there were 232 subjects age 65 or older, and 22 subjects age 75 or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other clinical experience has not identified differences in the responses between elderly and younger patients.

Clinical studies of NEUPOGEN in other approved indications (ie, bone marrow transplant recipients, PBPC mobilization, and SCN) did not include sufficient numbers of subjects aged 65 and older to determine whether elderly subjects respond differently from younger subjects.

In clinical trials involving over 350 patients receiving NEUPOGEN following nonmyeloablative cytotoxic chemotherapy‚ most adverse experiences were the sequelae of the underlying malignancy or cytotoxic chemotherapy. In all phase 2 and 3 trials‚ medullary bone pain‚ reported in 24% of patients‚ was the only consistently observed adverse reaction attributed to NEUPOGEN therapy. This bone pain was generally reported to be of mild-to-moderate severity‚ and could be controlled in most patients with non-narcotic analgesics; infrequently‚ bone pain was severe enough to require narcotic analgesics. Bone pain was reported more frequently in patients treated with higher doses (20 to 100 mcg/kg/day) administered IV‚ and less frequently in patients treated with lower SC doses of NEUPOGEN (3 to 10 mcg/kg/day).

In the randomized‚ double-blind‚ placebo-controlled trial of NEUPOGEN therapy following combination chemotherapy in patients (n = 207) with small cell lung cancer‚ the following adverse events were reported during blinded cycles of study medication (placebo or NEUPOGEN at 4 to 8 mcg/kg/day). Events are reported as exposure-adjusted since patients remained on double-blind NEUPOGEN a median of 3 cycles versus 1 cycle for placebo.

In this study‚ there were no serious‚ life-threatening‚ or fatal adverse reactions attributed to NEUPOGEN therapy. Specifically‚ there were no reports of flu-like symptoms‚ pleuritis‚ pericarditis‚ or other major systemic reactions to NEUPOGEN.

Spontaneously reversible elevations in uric acid‚ lactate dehydrogenase‚ and alkaline phosphatase occurred in 27% to 58% of 98 patients receiving blinded NEUPOGEN therapy following cytotoxic chemotherapy; increases were generally mild-to-moderate. Transient decreases in blood pressure (less than 90/60 mmHg)‚ which did not require clinical treatment‚ were reported in 7 of 176 patients in phase 3 clinical studies following administration of NEUPOGEN. Cardiac events (myocardial infarctions‚ arrhythmias) have been reported in 11 of 375 cancer patients receiving NEUPOGEN in clinical studies; the relationship to NEUPOGEN therapy is unknown. No evidence of interaction of NEUPOGEN with other drugs was observed in the course of clinical trials (see ).

There has been no evidence for the development of antibodies or of a blunted or diminished response to NEUPOGEN in treated patients‚ including those receiving NEUPOGEN daily for almost 2 years.

In a randomized phase 3 clinical trial, 259 patients received NEUPOGEN and 262 patients received placebo postchemotherapy. Overall, the frequency of all reported adverse events was similar in both the NEUPOGEN and placebo groups (83% vs 82% in Induction 1; 61% vs 64% in Consolidation 1). Adverse events reported more frequently in the NEUPOGEN-treated group included: petechiae (17% vs 14%), epistaxis (9% vs 5%), and transfusion reactions (10% vs 5%). There were no significant differences in the frequency of these events.

There were a similar number of deaths in each treatment group during induction (25 NEUPOGEN vs 27 placebo). The primary causes of death included infection (9 vs 18), persistent leukemia (7 vs 5), and hemorrhage (6 vs 3). Of the hemorrhagic deaths, 5 cerebral hemorrhages were reported in the NEUPOGEN group and 1 in the placebo group. Other serious nonfatal hemorrhagic events were reported in the respiratory tract (4 vs 1), skin (4 vs 4), gastrointestinal tract (2 vs 2), urinary tract (1 vs 1), ocular (1 vs 0), and other nonspecific sites (2 vs 1). While 19 (7%) patients in the NEUPOGEN group and 5 (2%) patients in the placebo group experienced severe or fatal hemorrhagic events, overall, hemorrhagic adverse events were reported at a similar frequency in both groups (40% vs 38%). The time to transfusion-independent platelet recovery and the number of days of platelet transfusions were similar in both groups.

In clinical trials‚ the reported adverse effects were those typically seen in patients receiving intensive chemotherapy followed by bone marrow transplant (BMT). The most common events reported in both control and treatment groups included stomatitis, nausea, and vomiting‚ generally of mild-to-moderate severity and were considered unrelated to NEUPOGEN. In the randomized studies of BMT involving 167 patients who received study drug‚ the following events occurred more frequently in patients treated with Filgrastim than in controls: nausea (10% vs 4%)‚ vomiting (7% vs 3%)‚ hypertension (4% vs 0%)‚ rash (12% vs 10%)‚ and peritonitis (2% vs 0%). None of these events were reported by the investigator to be related to NEUPOGEN. One event of erythema nodosum was reported moderate in severity and possibly related to NEUPOGEN.

Generally‚ adverse events observed in nonrandomized studies were similar to those seen in randomized studies‚ occurred in a minority of patients, and were of mild-to-moderate severity. In one study (n = 45)‚ 3 serious adverse events reported by the investigator were considered possibly related to NEUPOGEN. These included 2 events of renal insufficiency and 1 event of capillary leak syndrome. The relationship of these events to NEUPOGEN remains unclear since they occurred in patients with culture-proven infection with clinical sepsis who were receiving potentially nephrotoxic antibacterial and antifungal therapy.

In clinical trials‚ 126 patients received NEUPOGEN for PBPC mobilization. In this setting‚ NEUPOGEN was generally well tolerated. Adverse events related to NEUPOGEN consisted primarily of mild-to-moderate musculoskeletal symptoms‚ reported in 44% of patients. These symptoms were predominantly events of medullary bone pain (33%). Headache was reported related to NEUPOGEN in 7% of patients. Transient increases in alkaline phosphatase related to NEUPOGEN were reported in 21% of the patients who had serum chemistries measured; most were mild-to-moderate.

All patients had increases in neutrophil counts during mobilization‚ consistent with the biological effects of NEUPOGEN. Two patients had a WBC count greater than 100‚000/mm. No sequelae were associated with any grade of leukocytosis.

Sixty-five percent of patients had mild-to-moderate anemia and 97% of patients had decreases in platelet counts; 5 patients (out of 126) had decreased platelet counts to less than 50‚000/mm. Anemia and thrombocytopenia have been reported to be related to leukapheresis; however‚ the possibility that NEUPOGEN mobilization may contribute to anemia or thrombocytopenia has not been ruled out.

Mild-to-moderate bone pain was reported in approximately 33% of patients in clinical trials. This symptom was readily controlled with non-narcotic analgesics. Generalized musculoskeletal pain was also noted in higher frequency in patients treated with NEUPOGEN. Palpable splenomegaly was observed in approximately 30% of patients. Abdominal or flank pain was seen infrequently, and thrombocytopenia (less than 50‚000/mm) was noted in 12% of patients with palpable spleens. Fewer than 3% of all patients underwent splenectomy‚ and most of these had a prestudy history of splenomegaly. Fewer than 6% of patients had thrombocytopenia (less than 50‚000/mm) during NEUPOGEN therapy‚ most of whom had a pre-existing history of thrombocytopenia. In most cases‚ thrombocytopenia was managed by NEUPOGEN dose reduction or interruption. An additional 5% of patients had platelet counts between 50‚000 and 100‚000/mm. There were no associated serious hemorrhagic sequelae in these patients. Epistaxis was noted in 15% of patients treated with NEUPOGEN but was associated with thrombocytopenia in 2% of patients. Anemia was reported in approximately 10% of patients‚ but in most cases appeared to be related to frequent diagnostic phlebotomy‚ chronic illness, or concomitant medications. Other adverse events infrequently observed and possibly related to NEUPOGEN therapy were: injection site reaction‚ rash‚ hepatomegaly‚ arthralgia‚ osteoporosis‚ cutaneous vasculitis‚ hematuria/proteinuria‚ alopecia‚ and exacerbation of some pre-existing skin disorders (eg‚ psoriasis).

Cytogenetic abnormalities, transformation to MDS, and AML have been observed in patients treated with NEUPOGEN for SCN (see , : ). As of 31 December 1997, data were available from a postmarketing surveillance study of 531 SCN patients with an average follow-up of 4.0 years. Based on analysis of these data, the risk of developing MDS and AML appears to be confined to the subset of patients with congenital neutropenia. A life-table analysis of these data revealed that the cumulative risk of developing leukemia or MDS by the end of the 8th year of NEUPOGEN treatment in a patient with congenital neutropenia was 16.5% (95% C.I. = 9.8%, 23.3%); this represents an annual rate of approximately 2%. Cytogenetic abnormalities, most commonly involving chromosome 7, have been reported in patients treated with NEUPOGEN who had previously documented normal cytogenetics. It is unknown whether the development of cytogenetic abnormalities, MDS, or AML is related to chronic daily NEUPOGEN administration or to the natural history of congenital neutropenia. It is also unknown if the rate of conversion in patients who have not received NEUPOGENis different from that of patients who have received NEUPOGEN. Routine monitoring through regular CBCs is recommended for all SCN patients. Additionally, annual bone marrow and cytogenetic evaluations are recommended in all patients with congenital neutropenia (see ).

The following adverse reactions have been identified during postapproval of NEUPOGEN. 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.

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72
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Interactions

Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).