Clinical Trial ExperienceCancer Patients Receiving Myelosuppressive Chemotherapy

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 PRECAUTIONS). 

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 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.

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 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.

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%). 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/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.

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 splenomegaly 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 prestudy 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 SCN (see WARNINGS, PRECAUTIONS: Pediatric Use). 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 NEUPOGEN® is 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 LABORATORY MONITORING).

Postmarketing 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 rupture (see WARNINGS: Splenic Rupture) 
  * acute respiratory distress syndrome (ARDS) (see WARNINGS: Acute Respiratory Distress Syndrome) 
  * alveolar hemorrhage and hemoptysis (see WARNINGS: Alveolar Hemorrhage and Hemoptysis) 
  * sickle cell crisis (see WARNINGS: Sickle Cell Disorders) 
  * cutaneous vasculitis (see PRECAUTIONS: Cutaneous Vasculitis) 
  * Sweet’s syndrome (acute febrile neutrophilic dermatosis)