Filgrastim
Encyclopedia
Filgrastim is a granulocyte colony-stimulating factor
(G-CSF) analog used to stimulate the proliferation and differentiation of granulocyte
s. It is produced by recombinant DNA technology. The gene for human granulocyte colony-stimulating factor is inserted into the genetic material of Escherichia coli
. The G-CSF then produced by E. coli is only slightly different from G-CSF naturally made in humans.
It is marketed by Amgen
under the brand name Neupogen, Dr. Reddy's Laboratories
under the brand name Grafeel, Reliance Life Sciences
under the brand name Religrast, Zenotech Laboratories Limited under the brand name Nugraf, Raichem lifesciences under the brand name Shilgrast , Intas Biopharmaceuticals
under the brand name Neukine and Emcure biopharmaceuticals under the brand name Emgrast, CCL Pharmaceuticals (Pvt) Ltd under the brand name Grastin.
Apricus Biosciences
is currently developing and testing a product (under the brand name Nupen) which can deliver filgrastim through the skin to improve post-chemotherapy recovery of neutrophil counts.
(a low number of neutrophils), stimulating the bone marrow
to increase production of neutrophils. Causes of neutropenia include chemotherapy
and bone marrow transplantation.
Filgrastim is also used to increase the number of hematopoietic stem cells in the blood before collection by leukapheresis
for use in hematopoietic stem cell transplantation. It is produced by many companies worldwide.
s.
‚ 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 chart displays 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 ( < 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.
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.
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.
(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 non-randomized 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.
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 white blood cell count greater than 100‚000/mm3. 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/mm3. 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.
was observed in approximately 30% of patients. Abdominal or flank pain was seen infrequently, and thrombocytopenia ( less than 50‚000/mm3) was noted in 12% of patients with palpable spleens. Fewer than 3% of all patients underwent splenectomy
‚ and most of these had a pre-study history of splenomegaly. Fewer than 6% of patients had thrombocytopenia (less than 50‚000/mm3) 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/mm3. 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 severe chronic neutropenia. As of 31 December 1997, data were available from a post marketing surveillance study of 531 severe chronic neutropenia 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 Neupogen is different from that of patients who have received Neupogen. Routine monitoring through regular CBCs is recommended for all severe chronic neutropenia patients. Additionally, annual bone marrow and cytogenetic evaluations are recommended in all patients with congenital neutropenia (see Laboratory Monitoring).
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.
, serious allergic reactions (including a rash over the whole body, shortness of breath, wheezing, dizziness, swelling around the mouth or eyes, fast pulse, and sweating), alveolar
hemorrhage
, acute respiratory distress syndrome (ARDS)
, and hemoptysis
.
, 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.
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.
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.
due to other hematopoietic disorders (eg‚ myelodysplastic syndrome
) have not been established. Care should be taken to confirm the diagnosis of severe chronic neutropenia before initiating Neupogen therapy.
Myelodysplastic syndrome has been reported to occur in the natural history of congenital neutropenia
without cytokine therapy. Cytogenetic abnormalities and transformation to myelodysplastic syndrome have also been observed in patients treated with Neupogen for severe chronic neutropenia. Based on available data including a post-marketing surveillance study, the risk of developing myelodysplastic syndrome appears to be confined to the subset of patients with congenital neutropenia. Abnormal cytogenetics and myelodysplastic syndrome 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 myelodysplastic syndrome are unknown. If a patient with severe chronic neutropenia develops abnormal cytogenetics or myelodysplasia‚ the risks and benefits of continuing Neupogen should be carefully considered.
Granulocyte colony-stimulating factor
Granulocyte colony-stimulating factor is a colony-stimulating factor hormone. G-CSF is also known as colony-stimulating factor 3 ....
(G-CSF) analog used to stimulate the proliferation and differentiation of granulocyte
Granulocyte
Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. They are also called polymorphonuclear leukocytes because of the varying shapes of the nucleus, which is usually lobed into three segments...
s. It is produced by recombinant DNA technology. The gene for human granulocyte colony-stimulating factor is inserted into the genetic material of Escherichia coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
. The G-CSF then produced by E. coli is only slightly different from G-CSF naturally made in humans.
It is marketed by Amgen
Amgen
Amgen Inc. is an international biotechnology company headquartered in Thousand Oaks, California. Located in the Conejo Valley, Amgen is the world's largest independent biotech firm. The company employs approximately 17,000 staff members. Its products include Epogen, Aranesp, Enbrel, Kineret,...
under the brand name Neupogen, Dr. Reddy's Laboratories
Dr. Reddy's Laboratories
Dr. Reddy's Laboratories Ltd. is an integrated pharmaceutical company focused on providing medicines through its three business segments: Global Generics segment, Pharmaceutical Services and Active Ingredients segment and Proprietary Products segment. The company was founded by Dr...
under the brand name Grafeel, Reliance Life Sciences
Reliance Life Sciences
Reliance Life Sciences is a diversified and integrated biotechnology initiative of the Reliance group companies, India's largest private sector companies...
under the brand name Religrast, Zenotech Laboratories Limited under the brand name Nugraf, Raichem lifesciences under the brand name Shilgrast , Intas Biopharmaceuticals
Intas Biopharmaceuticals
Intas Biopharmaceuticals Ltd. is an Indian biotechnology company headquartered in Ahmedabad, India. Located in the Moraiya,Ahmedabad,it is one of the leading biosimilar product manufacturer in Asia....
under the brand name Neukine and Emcure biopharmaceuticals under the brand name Emgrast, CCL Pharmaceuticals (Pvt) Ltd under the brand name Grastin.
Apricus Biosciences
Apricus Biosciences
Apricus Biosciences is a San Diego based pharmaceutical company which develops products utilizing a permeation enhancer, the NexACT drug delivery technology to enable multi-route administration of compounds across numerous therapeutic classes....
is currently developing and testing a product (under the brand name Nupen) which can deliver filgrastim through the skin to improve post-chemotherapy recovery of neutrophil counts.
Therapeutic uses
Filgrastim is used to treat neutropeniaNeutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
(a low number of neutrophils), stimulating the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
to increase production of neutrophils. Causes of neutropenia include chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
and bone marrow transplantation.
Filgrastim is also used to increase the number of hematopoietic stem cells in the blood before collection by leukapheresis
Leukapheresis
Leukapheresis is a laboratory procedure in which white blood cells are separated from a sample of blood. It is a specific type of apheresis, the more general term for separating out one particular constituent of blood and returning the remainder to the circulation.Leukapheresis may be performed to...
for use in hematopoietic stem cell transplantation. It is produced by many companies worldwide.
Contraindications
Filgrastim should not be used in patients with known hypersensitivity to E. coli-derived proteinProtein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s.
Cancer Patients Receiving Myelosuppressive Chemotherapy
In clinical trials involving over 350 patients receiving Neupogen following nonmyeloablative cytotoxic chemotherapyChemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
‚ 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 chart displays 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 ( < 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.
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.
Patients With Acute Myeloid Leukemia
In a randomized phase 3 clinical trial, 259 patients received Neupogen and 262 patients received placebo post-chemotherapy. 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.
Cancer Patients Receiving Bone Marrow Transplant
In clinical trials‚ the reported adverse effects were those typically seen in patients receiving intensive chemotherapy followed by bone marrow transplantBone marrow transplant
Hematopoietic stem cell transplantation is the transplantation of multipotent hematopoietic stem cell or blood, usually derived from bone marrow, peripheral blood stem cells, or umbilical cord blood...
(BMT). The most common events reported in both control and treatment groups included stomatitis
Stomatitis
Stomatitis is an inflammation of the mucous lining of any of the structures in the mouth, which may involve the cheeks, gums, tongue, lips, throat, and roof or floor of the mouth...
, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
‚ 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
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
(4% vs 0%)‚ rash
Rash
A rash is a change of the skin which affects its color, appearance or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracked or blistered, swell and may be painful. The causes, and...
(12% vs 10%)‚ and peritonitis
Peritonitis
Peritonitis is an inflammation of the peritoneum, the serous membrane that lines part of the abdominal cavity and viscera. Peritonitis may be localised or generalised, and may result from infection or from a non-infectious process.-Abdominal pain and tenderness:The main manifestations of...
(2% vs 0%). None of these events were reported by the investigator to be related to Neupogen ®. One event of erythema nodosum
Erythema nodosum
Erythema nodosum is an inflammation of the fat cells under the skin characterized by tender red nodules or lumps that are usually seen on both shins...
was reported moderate in severity and possibly related to Neupogen.
Generally‚ adverse events observed in non-randomized 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
Capillary leak syndrome
Capillary leak syndrome is a rare medical conditioncharacterized by self-reversing episodes during which the endothelial cells which line the capillaries are thought to separate for a few days, allowing for a leakage of fluid from the circulatory system to the interstitial space, resulting in a...
. 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.
Cancer Patients Undergoing Peripheral Blood Progenitor Cell Collection and 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%). HeadacheHeadache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
was reported related to Neupogen in 7% of patients. Transient increases in alkaline phosphatase
Alkaline phosphatase
Alkaline phosphatase is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. The process of removing the phosphate group is called dephosphorylation...
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 white blood cell count greater than 100‚000/mm3. No sequelae were associated with any grade of leukocytosis
Leukocytosis
Leukocytosis is a raised white blood cell count above the normal range in the blood. It is frequently a sign of an inflammatory response, most commonly the result of infection, and is observed in certain parasitic infections...
.
Sixty-five percent of patients had mild-to-moderate anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
and 97% of patients had decreases in platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
counts; 5 patients (out of 126) had decreased platelet counts to less than 50‚000/mm3. Anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
and thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
have been reported to be related to leukapheresis
Leukapheresis
Leukapheresis is a laboratory procedure in which white blood cells are separated from a sample of blood. It is a specific type of apheresis, the more general term for separating out one particular constituent of blood and returning the remainder to the circulation.Leukapheresis may be performed to...
; however‚ the possibility that Neupogen mobilization may contribute to anemia or thrombocytopenia has not been ruled out.
Patients With Severe Chronic Neutropenia
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 splenomegalySplenomegaly
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
was observed in approximately 30% of patients. Abdominal or flank pain was seen infrequently, and thrombocytopenia ( less than 50‚000/mm3) was noted in 12% of patients with palpable spleens. Fewer than 3% of all patients underwent splenectomy
Splenectomy
A splenectomy is a surgical procedure that partially or completely removes the spleen.-Indications:The spleen, similar in structure to a large lymph node, acts as a blood filter. Current knowledge of its purpose includes the removal of old red blood cells and platelets, and the detection and fight...
‚ and most of these had a pre-study history of splenomegaly. Fewer than 6% of patients had thrombocytopenia (less than 50‚000/mm3) during Neupogen therapy‚ most of whom had a pre-existing history of thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
. 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/mm3. 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
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
was reported in approximately 10% of patients‚ but in most cases appeared to be related to frequent diagnostic phlebotomy
Phlebotomy
Phlebotomy is the process of making an incision in a vein.It is associated with the following concepts:* Venipuncture, the practice of collecting venous blood samples* The main practice of a phlebotomist, an individual trained to draw blood...
‚ chronic illness, or concomitant medications. Other adverse events infrequently observed and possibly related to Neupogen therapy were: injection site reaction‚ rash‚ hepatomegaly
Hepatomegaly
Hepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...
‚ arthralgia
Arthralgia
Arthralgia literally means joint pain; it is a symptom of injury, infection, illnesses or an allergic reaction to medication....
‚ osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
‚ cutaneous vasculitis‚ hematuria
Hematuria
In medicine, hematuria, or haematuria, is the presence of red blood cells in the urine. It may be idiopathic and/or benign, or it can be a sign that there is a kidney stone or a tumor in the urinary tract , ranging from trivial to lethal...
/proteinuria
Proteinuria
Proteinuria means the presence of anexcess of serum proteins in the urine. The protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine , retrograde ejaculation, pneumaturia due to a fistula, or drugs such as pyridium.- Causes...
‚ alopecia
Alopecia
Alopecia means loss of hair from the head or body. Alopecia can mean baldness, a term generally reserved for pattern alopecia or androgenic alopecia. Compulsive pulling of hair can also produce hair loss. Hairstyling routines such as tight ponytails or braids may induce Traction alopecia. Both...
‚ and exacerbation of some pre-existing skin disorders (eg‚ psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
).
Cytogenetic abnormalities, transformation to MDS, and AML have been observed in patients treated with Neupogen for severe chronic neutropenia. As of 31 December 1997, data were available from a post marketing surveillance study of 531 severe chronic neutropenia 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 Neupogen is different from that of patients who have received Neupogen. Routine monitoring through regular CBCs is recommended for all severe chronic neutropenia patients. Additionally, annual bone marrow and cytogenetic evaluations are recommended in all patients with congenital neutropenia (see Laboratory Monitoring).
Post-marketing Experience
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.- splenic ruptureRuptured spleenRupture of the capsule of the spleen, an organ in the upper left part of the abdomen, is a situation that requires immediate medical attention. The rupture of a normal spleen can be caused by trauma, such as a car accident.-Function In the Body:...
- acute respiratory distress syndromeAcute respiratory distress syndromeAcute respiratory distress syndrome , also known as respiratory distress syndrome or adult respiratory distress syndrome is a serious reaction to various forms of injuries to the lung....
(ARDS) - alveolar hemorrhage and hemoptysisHemoptysisHemoptysis or haemoptysis is the expectoration of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis is the expectoration (coughing up) of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis ...
- sickle cell crisis
- cutaneous vasculitisCutaneous small-vessel vasculitisCutaneous small-vessel vasculitis is inflammation of small blood vessels , characterized by palpable purpura. It is the most common vasculitis seen in clinical practice...
- Sweet's syndrome (acute febrile neutrophilic dermatosis)
Drug Interactions
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.
Women Pregnant or Nursing
Neupogen has not been studied in pregnant women and its effects on unborn babies is unknown. If taking Neupogen while pregnant, it is possible that traces of the drug could be found in the baby's blood. It is not known if Neupogen can get into human breast milk.Adverse effects
The most commonly observed adverse effect is mild-to-moderate bone pain after repeated administration and local skin reactions at the site of injection. Persons with sickle cell disorders may suffer sickle cell crisis after receiving Neupogen. Other adverse effects include spleen ruptureRuptured spleen
Rupture of the capsule of the spleen, an organ in the upper left part of the abdomen, is a situation that requires immediate medical attention. The rupture of a normal spleen can be caused by trauma, such as a car accident.-Function In the Body:...
, serious allergic reactions (including a rash over the whole body, shortness of breath, wheezing, dizziness, swelling around the mouth or eyes, fast pulse, and sweating), alveolar
Pulmonary alveolus
An alveolus is an anatomical structure that has the form of a hollow cavity. Found in the lung parenchyma, the pulmonary alveoli are the dead ends of the respiratory tree, which outcrop from either alveolar sacs or alveolar ducts, which are both sites of gas exchange with the blood as well...
hemorrhage
Bleeding
Bleeding, technically known as hemorrhaging or haemorrhaging is the loss of blood or blood escape from the circulatory system...
, acute respiratory distress syndrome (ARDS)
Acute respiratory distress syndrome
Acute respiratory distress syndrome , also known as respiratory distress syndrome or adult respiratory distress syndrome is a serious reaction to various forms of injuries to the lung....
, and hemoptysis
Hemoptysis
Hemoptysis or haemoptysis is the expectoration of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis is the expectoration (coughing up) of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis ...
.
Allergic Reaction
Allergic-type reactions occurring on initial or subsequent treatment have been reported in < 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. 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.Spleen Rupture
Splenic ruptureRuptured spleen
Rupture of the capsule of the spleen, an organ in the upper left part of the abdomen, is a situation that requires immediate medical attention. The rupture of a normal spleen can be caused by trauma, such as a car accident.-Function In the Body:...
, 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)
Acute respiratory distress syndrome (ARDS)Acute respiratory distress syndrome
Acute respiratory distress syndrome , also known as respiratory distress syndrome or adult respiratory distress syndrome is a serious reaction to various forms of injuries to the lung....
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 and Hemoptysis
AlveolarPulmonary alveolus
An alveolus is an anatomical structure that has the form of a hollow cavity. Found in the lung parenchyma, the pulmonary alveoli are the dead ends of the respiratory tree, which outcrop from either alveolar sacs or alveolar ducts, which are both sites of gas exchange with the blood as well...
hemorrhage
Bleeding
Bleeding, technically known as hemorrhaging or haemorrhaging is the loss of blood or blood escape from the circulatory system...
manifesting as pulmonary infiltrates and hemoptysis
Hemoptysis
Hemoptysis or haemoptysis is the expectoration of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis is the expectoration (coughing up) of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis ...
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.
Sickle Cell Disorders
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.Patients With Severe Chronic Neutropenia
The safety and efficacy of Neupogen in the treatment of neutropeniaNeutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
due to other hematopoietic disorders (eg‚ myelodysplastic syndrome
Myelodysplastic syndrome
The myelodysplastic syndromes are a diverse collection of hematological medical conditions that involve ineffective production of the myeloid class of blood cells....
) have not been established. Care should be taken to confirm the diagnosis of severe chronic neutropenia before initiating Neupogen therapy.
Myelodysplastic syndrome has been reported to occur in the natural history of congenital neutropenia
Kostmann syndrome
Kostmann syndrome, also known as severe congenital neutropenia, autosomal recessive type 3 and Kostmann disease, is a rare autosomal recessive form of severe chronic neutropenia usually detected soon after birth...
without cytokine therapy. Cytogenetic abnormalities and transformation to myelodysplastic syndrome have also been observed in patients treated with Neupogen for severe chronic neutropenia. Based on available data including a post-marketing surveillance study, the risk of developing myelodysplastic syndrome appears to be confined to the subset of patients with congenital neutropenia. Abnormal cytogenetics and myelodysplastic syndrome have been associated with the eventual development of myeloid leukemia
Myeloid leukemia
Myeloid leukemia is a type of leukemia affecting myeloid tissue.Types include:* Acute myeloid leukemia* Chronic myelogenous leukemia...
. The effect of Neupogen on the development of abnormal cytogenetics and the effect of continued Neupogen administration in patients with abnormal cytogenetics or myelodysplastic syndrome are unknown. If a patient with severe chronic neutropenia develops abnormal cytogenetics or myelodysplasia‚ the risks and benefits of continuing Neupogen should be carefully considered.