Neupogen Side Effects

Please note - some side effects for Neupogen may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Neupogen - for the Consumer

Neupogen

All medicines may cause side effects, but many people have no, or minor side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Neupogen:

Bone or muscle pain or ache; cough; headache; nausea; nosebleed; skeletal/muscle pain; vomiting.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain; coughing up blood; diarrhea; dizziness; fast or irregular heartbeat; fast or shallow breathing; fever; lump, swelling, redness, or bruising at an injection site; mouth sores; redness, swelling, or pain around a cut or sore; severe weakness; shortness of breath; shoulder pain; sore throat; stomach pain; sudden increased sweating; wheezing.

Neupogen Side Effects - for the Professional

Neupogen

Clinical Trial Experience

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 (< 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.

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 > 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 < 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.

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 (< 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 (< 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. 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.

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

Side Effects by Body System

General

Filgrastim generally has been well tolerated. Whole body symptoms have included neutropenic fever (13%), fatigue (11%), generalized weakness (4%), and unspecified pain (2%). Many patients receiving filgrastim have had serious underlying conditions requiring concurrent medications associated with high toxicity. It is sometimes difficult to discern true drug toxicity from disease activity.

Musculoskeletal

Musculoskeletal symptoms have been the most frequently reported adverse effects of filgrastim therapy. Bone pain has been reported in approximately 22% of patients. Reactivation of pseudogout occurred in a patient receiving chemotherapy.

Bone pain associated with filgrastim usually has localized in the lower back, posterior iliac crests, and sternum. Bone pain primarily occurred at initiation of therapy due to a transient increases in white blood cell (WBC) count, 2 to 3 days before a rise in peripheral blood neutrophils, and occurred more frequently with higher dosages. Analgesics may be helpful; however, pain may resolve with continued therapy and generally resolves within a few hours following discontinuation of therapy.

Hematologic

A case report described an acute arterial thrombosis thought to be due to filgrastim-induced platelet aggregation.

Hematologic changes associated with filgrastim occasionally have included petechiae, thrombocytopenia, anemia, myelodysplasia, and myeloid leukemia. White blood cell (WBC) counts equal to or greater than 100,000/mm3, without evidence of adverse effects, have occurred in approximately 2% of patients undergoing myelosuppressive chemotherapy. Results from treatment of HIV-infected patients with filgrastim (in combination with highly active antiretroviral therapy) have shown increases in the concentration of CD4, CD8 and NK cells without changes in the virus load.

Dermatologic

Sweet syndrome (acute febrile neutropenic dermatosis), characterized by fever, leukocytosis, neutrophilia, painful and red skin plaques, and histological verification of dermal invasion by mature granulocytes, has occurred during filgrastim therapy. In one case, a woman who was treated for chemotherapy-related neutropenia after 3 days of 5 mcg/kg filgrastim via subcutaneous injection noted painful red plaques in an arm area affected by postmastectomy lymphedema. Biopsy confirmed dermal granulocyte infiltration without vasculitis. Following filgrastim discontinuation, the lesions rapidly healed. The authors speculated that poor granulocyte clearance by damaged lymphatics promoted Sweet syndrome in this patient.

Dermatologic reactions associated with filgrastim have included alopecia (18%), generalized maculopapular rash (6%), reversible exacerbations of acne, and Sweet's syndrome. Filgrastim administration has also been associated with rare exacerbations of psoriasis and vasculitis.

Hepatic

Hepatic effects associated with filgrastim have included transient increases in alkaline phosphatase and lactate dehydrogenase in 28% to 57% of patients.

Cardiovascular

Cardiovascular effects of transient hypotension has been reported with filgrastim administration, primarily associated with intravenous administration. Chest pain was reported by 5% of patients receiving filgrastim following myelosuppressive chemotherapy.

Hypersensitivity

Hypersensitivity-type reactions, primarily associated with intravenous (IV) administration, have been reported. Symptoms have frequently involved at least two body systems, most often dermatologic (rash, urticaria, facial edema), respiratory (wheezing, dyspnea), or cardiovascular (hypotension, bradycardia). Anaphylaxis following a first dose of filgrastim has been reported.

Renal

An 18-year-old male undergoing peripheral blood stem cell transplantation for non-Hodgkin's lymphoma received 150 mcg/day of filgrastim on day 17 of chemotherapy. On day 5 of filgrastim administration the plasma creatinine rose from approximately 0.6 mg/dl to 1.8 mg/dL with accompanying increases in white blood cell (WBC) counts and lactic dehydrogenase (LDH) levels. A slight decrease in urine volume was noted. Discontinuation of filgrastim lead to rapid renal function recovery. Rechallenge at a reduced filgrastim dosage (75 mcg/day) failed to result in recurrence of renal deterioration. The authors suspected renal leukostasis during filgrastim therapy may have precipitated the adverse renal effects.

Rarely, renal adverse effects have occurred. A case report of reversible renal impairment with elevated serum creatinine levels has been reported.

Endocrine

Rarely, endocrine reactions, such as reversible clinical hypothyroidism, have been reported.

A case report describes a woman without a history of thyroid disease who received 10 mcg/kg filgrastim subcutaneously on days 3 through 13 of each cycle as adjunct to chemotherapy for breast cancer. Chemotherapy consisted of doxorubicin and cyclophosphamide. The patient developed symptoms of clinical hypothyroidism without thyrotropin receptor antibodies during the third cycle of filgrastim and required thyroid replacement for 2 months. Thyroid function returned to baseline status 10 weeks following discontinuation of filgrastim and chemotherapy drugs were continued without effect on thyroid function.

Local

Local reactions have included bruising and erythema at the injection site.

Metabolic

Metabolic changes have included reversible increases in uric acid concentrations in 28% to 57% of patients.

Oncologic

Oncologic effects may occur due to filgrastim effect as a growth factor with any myeloid tumor.

Gastrointestinal

Gastrointestinal symptoms of nausea and vomiting have been reported in 57% of patients who received filgrastim following myelosuppressive chemotherapy. Diarrhea (14%), mucositis (12%), anorexia (9%), constipation (5%), stomatitis (5%), and sore throat (4%) have been reported.

Respiratory

Respiratory symptoms of dyspnea (9%), cough (6%) and alveolar hemorrhage and hemoptysis have been reported.

Nervous system

Nervous system side effects have been characterized by headaches in 7% of patients.

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