Biocilin

What are the side effects you encounter while taking this medicine?
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Biocilin uses



Warnings and Precautions: Glomerulonephritis (5.5) 07/2015

1 INDICATIO NS AND USAGE

Biocilin is a leukocyte growth factor indicated to

1.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy

Biocilin 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 Clinical Studies ( 14.1 )].

1.2 Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy

Biocilin is indicated for reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia [see Clinical Studies ( 14.2 )].

1.3 Patients with Cancer Undergoing Bone Marrow Transplantation

Biocilin is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae‚ e.g.‚ febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation [see Clinical Studies ( 14.3 )].

1.4 Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy

Biocilin is indicated for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis .

1.5 Patients with Severe Chronic Neutropenia

Biocilin is indicated for chronic administration to reduce the incidence and duration of sequelae of neutropenia (e.g.‚ fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia [see Clinical Studies ( 14.5 )].

1.6 Patients Acutely Exposed to Myelosuppressive Doses of Radiation

NEUPOGEN is indicated to increase survival in patients acutely exposed to myelosuppressive doses of radiation [see Clinical Studies ( 14.6 )].

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2 DOSAGE AND ADMINISTRATION

2.1 Dosage in Patients with Cancer Receiving Myelosuppressive Chemotherapy or Induction and/or Consolidation Chemotherapy for AML

The recommended starting dosage of Biocilin is 5 mcg/kg/day‚ administered as a single daily injection by subcutaneous injection‚ by short intravenous infusion (15 to 30 minutes)‚ or by continuous intravenous infusion. Obtain a complete blood count (CBC) and platelet count before instituting Biocilin therapy and monitor twice weekly during therapy. Consider dose escalation in increments of 5 mcg/kg for each chemotherapy cycle‚ according to the duration and severity of the absolute neutrophil count (ANC) nadir. Recommend stopping Biocilin if the ANC increases beyond 10‚000/mm3 [see Warnings and Precautions ( 5.10 )].

Administer NEUPOGEN at least 24 hours after cytotoxic chemotherapy. Do not administer Biocilin within the 24-hour period prior to chemotherapy [see Warnings and Precautions ( 5.13 )]. A transient increase in neutrophil count is typically seen 1 to 2 days after initiation of Biocilin therapy. Therefore, to ensure a sustained therapeutic response‚ administer Biocilin daily for up to 2 weeks or until the ANC has reached 10‚000/mm3 following the expected chemotherapy-induced neutrophil nadir. The duration of Biocilin therapy needed to attenuate chemotherapy-induced neutropenia may be dependent on the myelosuppressive potential of the chemotherapy regimen employed.

2.2 Dosage in Patients with Cancer Undergoing Bone Marrow Transplantation

The recommended dosage of Biocilin following bone marrow transplantation is 10 mcg/kg/day given as an intravenous infusion no longer than 24 hours. Administer the first dose of NEUPOGEN at least 24 hours after cytotoxic chemotherapy and at least 24 hours after bone marrow infusion. Monitor CBCs and platelet counts frequently following marrow transplantation.

During the period of neutrophil recovery‚ titrate the daily dosage of NEUPOGEN against the neutrophil response.

Absolute Neutrophil Count Biocilin Dos ag e Adjustment
When ANC greater than 1000/mm3 for 3 consecutive days Reduce to 5 mcg/kg/daya
Then, if ANC remains greater than 1000/mm3

for 3 more consecutive days

Discontinue Biocilin
Then, if ANC decreases to less than 1000/mm3 Resume at 5 mcg/kg/day

a If ANC decreases to less than 1000/mm3 at any time during the 5 mcg/kg/day administration‚ increase Biocilin to 10 mcg/kg/day‚ and then follow the above steps.

2.3 Dosage in Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy

The recommended dosage of Biocilin for the mobilization of autologous peripheral blood progenitor cells (PBPC) is 10 mcg/kg/day given by subcutaneous injection. Administer Biocilin for at least 4 days before the first leukapheresis procedure and continue until the last leukapheresis. Although the optimal duration of Biocilin administration and leukapheresis schedule have not been established‚ administration of Biocilin for 6 to 7 days with leukaphereses on days 5‚ 6‚ and 7 was found to be safe and effective [see Clinical Studies ( 14.4 )]. Monitor neutrophil counts after 4 days of NEUPOGEN‚ and discontinue Biocilin if the white blood cell (WBC) count rises to greater than 100‚000/mm3.

2.4 Dosage in Patients with Severe Chronic Neutropenia

Prior to starting Biocilin in patients with suspected chronic neutropenia, confirm the diagnosis of severe chronic neutropenia by evaluating serial CBCs with differential and platelet counts‚ and evaluating bone marrow morphology and karyotype. The use of Biocilin prior to confirmation of a correct diagnosis 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.

The recommended starting dosage in patients with Congenital Neutropenia is 6 mcg/kg as a twice daily subcutaneous injection and the recommended starting dosage in patients with Idiopathic or Cyclic Neutropenia is 5 mcg/kg as a single daily subcutaneous injection.

Dos ag e Adjustments in Patients with Severe Chronic Neutropenia

Chronic daily administration is required to maintain clinical benefit. Individualize the dosage based on the patient’s clinical course as well as ANC. In the SCN postmarketing surveillance study, the reported median daily doses of Biocilin were: 6 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 Biocilin greater than or equal to 100 mcg/kg/day.

Monitor CBCs for Dosage Adjustments

During the initial 4 weeks of Biocilin therapy and during the 2 weeks following any dosage adjustment‚ monitor CBCs with differential and platelet counts. Once a patient is clinically stable‚ monitor CBCs with differential and platelet counts monthly during the first year of treatment. Thereafter, if the patient is clinically stable, less frequent routine monitoring is recommended.

2.5 Dosage in Patients Acutely Exposed to Myelosuppressive Doses of Radiation (Hematopoietic Syndrome of Acute Radiation Syndrome)

The recommended dose of Biocilin is 10 mcg/kg as a single daily subcutaneous injection for patients exposed to myelosuppressive doses of radiation. Administer Biocilin as soon as possible after suspected or confirmed exposure to radiation doses greater than 2 gray (Gy).

Estimate a patient’s absorbed radiation dose (i.e., level of radiation exposure) based on information from public health authorities, biodosimetry if available, or clinical findings such as time to onset of vomiting or lymphocyte depletion kinetics.

Obtain a baseline CBC and then serial CBCs approximately every third day until the ANC remains greater than 1,000/mm3 for 3 consecutive CBCs. Do not delay administration of Biocilin if a CBC is not readily available.

Continue administration of Biocilin until the ANC remains greater than 1,000/mm3 for 3 consecutive CBCs or exceeds 10,000/mm3 after a radiation-induced nadir.

2.6 Important Administration Instructions

Biocilin is supplied in single-dose vials (for subcutaneous use or intravenous infusion) and single-dose prefilled syringes (for subcutaneous use) [see Dosage Forms and Strengths ( 3 )]. Prior to use‚ remove the vial or prefilled syringe from the refrigerator and allow Biocilin to reach room temperature for a minimum of 30 minutes and a maximum of 24 hours. Discard any vial or prefilled syringe left at room temperature for greater than 24 hours. Visually inspect Biocilin for particulate matter and discoloration prior to administration (the solution is clear and colorless). Do not administer Biocilin if particulates or discoloration are observed.

Discard unused portion of Biocilin in vials or prefilled syringes; do not re-enter the vial. Do not save unused drug for later administration.

Subcutaneous Injection

Inject Biocilin subcutaneously in the outer area of upper arms, abdomen, thighs, or upper outer areas of the buttock. If patients or caregivers are to administer Biocilin, instruct them in appropriate injection technique and ask them to follow the subcutaneous injection procedures in the Instructions for Use for the vial or prefilled syringe [see Patient Counseling Information ( 17 )].

Training by the healthcare provider should aim to demonstrate to those patients and caregivers how to measure the dose of Biocilin, and the focus should be on ensuring that a patient or caregiver can successfully perform all of the steps in the Instructions for Use for the vial or prefilled syringe. If a patient or caregiver is not able to demonstrate that they can measure the dose and administer the product successfully, you should consider whether the patient is an appropriate candidate for self-administration of NEUPOGEN or whether the patient would benefit from a different NEUPOGEN presentation. If a patient or caregiver experiences difficulty measuring the required dose, especially if it is other than the entire contents of the NEUPOGEN prefilled syringe, use of the Biocilin vial may be considered.

If the patient or caregiver misses a dose of Biocilin, instruct them to contact their healthcare provider.

Administration Instructions for the Prefilled Syringe

Persons with latex allergies should not administer the NEUPOGEN prefilled syringe, because the needle cap contains dry natural rubber (derived from latex).

Administration Instructions for Dilution (Vial Only)

If required for intravenous administration‚ Biocilin (vial only) may be diluted in 5% Dextrose Injection, USP from a concentration of 300 mcg/mL to 5 mcg/mL (do not dilute to a final concentration less than 5 mcg/mL). Biocilin diluted to concentrations from 5 mcg/mL to 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 Injection, USP or 5% Dextrose plus Albumin (Human)‚ Biocilin is compatible with glass bottles‚ polyvinyl chloride (PVC) and polyolefin intravenous bags‚ and polypropylene syringes. Do not dilute with saline at any time because the product may precipitate.

Diluted Biocilin solution can be stored at room temperature for up to 24 hours. This 24 hour time period includes the time during room temperature storage of the infusion solution and the duration of the infusion.

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3 DOSAGE FORMS AND STRENGTHS

Vial:


Prefilled Syringe:


Vial


Prefilled Syringe

4 CONTRAINDICATIONS

Biocilin is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as Biocilin or pegfilgrastim [see Warnings and Precautions ( 5.3 )] .

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5 WARNINGS AND PRECAUTIONS

5.1 Splenic Rupture

Splenic rupture, including fatal cases, has been reported following the administration of Biocilin. Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture.

5.2 Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome has been reported in patients receiving Biocilin. Evaluate patients who develop fever and lung infiltrates or respiratory distress for ARDS. Discontinue Biocilin in patients with ARDS.

5.3 Serious Allergic Reactions

Serious allergic reactions, including anaphylaxis, have been reported in patients receiving Biocilin. The majority of reported events occurred upon initial exposure. Provide symptomatic treatment for allergic reactions. Allergic reactions, including anaphylaxis, in patients receiving Biocilin can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Biocilin in patients with serious allergic reactions. Biocilin is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as Biocilin or pegfilgrastim.

5.4 Sickle Cell Disorders

Sickle cell crisis, in some cases fatal, has been reported with the use of Biocilin in patients with sickle cell trait or sickle cell disease.

5.5 Glomerulonephritis

Glomerulonephritis has occurred in patients receiving Biocilin. The diagnoses were based upon azotemia, hematuria, proteinuria, and renal biopsy. Generally, events of glomerulonephritis resolved after dose reduction or discontinuation of Biocilin. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose-reduction or interruption of Biocilin.

5.6 Alveolar Hemorrhage and Hemoptysis

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

5.7 Capillary Leak Syndrome

Capillary leak syndrome has been reported after G-CSF administration, including Biocilin, and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care.

5.8 Patients with Severe Chronic Neutropenia

Confirm the diagnosis of SCN before initiating Biocilin therapy.

Myelodysplastic syndrome (MDS) and acute myelogenous leukemia (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 Biocilin 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. 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 Biocilin 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 Biocilin should be carefully considered.

5.9 Thrombocytopenia

Thrombocytopenia has been reported in patients receiving Biocilin. Monitor platelet counts.

5.10 Leukocytosis

Patients with Cancer Receiving Myelosuppressive Chemotherapy

White blood cell counts of 100‚000/mm3 or greater were observed in approximately 2% of patients receiving Biocilin at dosages above 5 mcg/kg/day. In patients with cancer receiving Biocilin as an adjunct to myelosuppressive chemotherapy‚ to avoid the potential risks of excessive leukocytosis‚ it is recommended that Biocilin therapy be discontinued if the ANC surpasses 10‚000/mm3 after the chemotherapy-induced ANC nadir has occurred. Monitor CBCs at least twice weekly during therapy. Dosages of Biocilin that increase the ANC beyond 10‚000/mm3 may not result in any additional clinical benefit. In patients with cancer receiving myelosuppressive chemotherapy‚ discontinuation of Biocilin therapy usually resulted in a 50% decrease in circulating neutrophils within 1 to 2 days‚ with a return to pretreatment levels in 1 to 7 days.

Peripheral Blood Progenitor Cell Collection and Therapy

During the period of administration of Biocilin for PBPC mobilization in patients with cancer, discontinue Biocilin if the leukocyte count rises to > 100,000/mm3.

5.11 Cutaneous Vasculitis

Cutaneous vasculitis has been reported in patients treated with Biocilin. In most cases‚ the severity of cutaneous vasculitis was moderate or severe. Most of the reports involved patients with SCN receiving long-term Biocilin therapy. Hold Biocilin therapy in patients with cutaneous vasculitis. Biocilin may be started at a reduced dose when the symptoms resolve and the ANC has decreased.

5.12 Potential Effect on Malignant Cells

Biocilin is a growth factor that primarily stimulates neutrophils. The granulocyte-colony-stimulating factor receptor through which Biocilin acts has also been found on tumor cell lines. The possibility that Biocilin acts as a growth factor for any tumor type cannot be excluded. The safety of Biocilin in chronic myeloid leukemia (CML) and myelodysplasia has not been established.

When Biocilin 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.

5.13 Simultaneous Use with Chemotherapy and Radiation Therapy Not Recommended

The safety and efficacy of Biocilin 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 Biocilin in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy [see Dosage and Administration ( 2.2 )].

The safety and efficacy of NEUPOGEN have not been evaluated in patients receiving concurrent radiation therapy. Avoid the simultaneous use of Biocilin with chemotherapy and radiation therapy.

5.14 Nuclear Imaging

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.

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6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:


Most common adverse reactions in patients:



To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adverse Reactions in Patients with Cancer Receiving Myelosuppressive Chemotherapy

The following adverse reaction data in Table 2 are from three randomized, placebo-controlled studies in patients with:


A total of 451 patients were randomized to receive subcutaneous Biocilin 230 mcg/m2 (Study 1), 240 mcg/m2 (Study 2) or 4 or 5 mcg/kg/day (Study 3) (n = 294) or placebo (n = 157). The patients in these studies were median age 61 (range 29 to 78) years and 64% were male. The ethnicity was 95% Caucasian, 4% African American, and 1% Asian.

System Organ Class

Preferred Term

Biocilin

(N = 294)

Placebo

(N = 157)

Blood and lymphatic system disorders
Thrombocytopenia 38% 29%
Gastrointestinal disorders
Nausea 43% 32%
General disorders and administration site conditions
Pyrexia 48% 29%
Chest pain 13% 6%
Pain 12% 6%
Fatigue 20% 10%
Musculoskeletal and connective tissue disorders
Back pain 15% 8%
Arthralgia 9% 2%
Bone pain 11% 6%
Pain in extremity* 7% 3%
Nervous system disorders
Dizziness 14% 3%
Respiratory, thoracic and mediastinal disorders
Cough 14% 8%
Dyspnea 13% 8%
Skin and subcutaneous tissue disorders
Rash 14% 5%
Investigations
Blood lactate dehydrogenase increased 6% 1%
Blood alkaline phosphatase increased 6% 1%

* Percent difference (NEUPOGEN – Placebo) was 4%.

Adverse events with ≥ 5% higher incidence in Biocilin patients compared to placebo and associated with the sequelae of the underlying malignancy or cytotoxic chemotherapy delivered included anemia, constipation, diarrhea, oral pain, vomiting, asthenia, malaise, edema peripheral, hemoglobin decreased, decreased appetite, oropharyngeal pain, and alopecia.

Adverse Reactions in Patients with Acute Myeloid Leukemia

Adverse reaction data below are from a randomized, double-blind, placebo-controlled study in patients with AML (Study 4) who received an induction chemotherapy regimen of intravenous daunorubicin days 1, 2, and 3; cytosine arabinoside days 1 to 7; and etoposide days 1 to 5 and up to 3 additional courses of therapy (induction 2, and consolidation 1, 2) of intravenous daunorubicin, cytosine arabinoside, and etoposide. The safety population included 518 patients randomized to receive either 5 mcg/kg/day Biocilin (n = 257) or placebo (n = 261). The median age was 54 (range 16 to 89) years and 54% were male.

Adverse reactions with ≥ 2% higher incidence in Biocilin patients compared to placebo included epistaxis, back pain, pain in extremity, erythema, and rash maculo-papular.

Adverse events with ≥ 2% higher incidence in Biocilin patients compared to placebo and associated with the sequelae of the underlying malignancy or cytotoxic chemotherapy included diarrhea, constipation, and transfusion reaction.

Adverse Reactions in Patients with Cancer Undergoing Bone Marrow Transplantation

The following adverse reaction data are from one randomized, no treatment-controlled study in patients with acute lymphoblastic leukemia or lymphoblastic lymphoma receiving high-dose chemotherapy (cyclophosphamide or cytarabine, and melphalan) and total body irradiation (Study 5) and one randomized, no treatment controlled study in patients with Hodgkin's disease (HD) and NHL undergoing high-dose chemotherapy and autologous bone marrow transplantation (Study 6). Patients receiving autologous bone marrow transplantation only were included in the analysis. A total of 100 patients received either 30 mcg/kg/day as a 4 hour infusion (Study 5) or 10 mcg/kg/day or 30 mcg/kg/day as a 24 hour infusion (Study 6) Biocilin (n = 72), no treatment control or placebo (n = 28). The median age was 30 (range 15 to 57) years, 57% were male.

Adverse reactions with ≥ 5% higher incidence in Biocilin patients compared to patients receiving no Biocilin included rash and hypersensitivity.

Adverse reactions in patients receiving intensive chemotherapy followed by autologous BMT with ≥ 5% higher incidence in Biocilin patients compared to patients receiving no Biocilin included thrombocytopenia, anemia, hypertension, sepsis, bronchitis, and insomnia.

Adverse Reactions in Patients with Cancer Undergoing Autologous Peripheral Blood Progenitor Cell Collection

The adverse reaction data in Table 3 are from a series of 7 trials in patients with cancer undergoing mobilization of autologous peripheral blood progenitor cells for collection by leukapheresis. Patients (n = 166) in all these trials underwent a similar mobilization/collection regimen: Biocilin was administered for 6 to 8 days‚ in most cases the apheresis procedure occurred on days 5‚ 6, and 7. The dosage of Biocilin ranged between 5 to 30 mcg/kg/day and was administered subcutaneously by injection or continuous infusion. The median age was 39 (range 15 to 67) years, and 48% were male.

System Organ Class

Preferred Term

Mobilization Phase

(N = 166)

Musculoskeletal and connective tissue disorders
Bone pain 30%
General disorders and administration site conditions
Pyrexia 16%
Investigations
Blood alkaline phosphatase increased 11%
Nervous system disorders
Headache 10%

Adverse Reactions in Patients with Severe Chronic Neutropenia

The following adverse reaction data were identified in a randomized, controlled study in patients with SCN receiving Biocilin (Study 7). 123 patients were randomized to a 4 month observation period followed by subcutaneous Biocilin treatment or immediate subcutaneous Biocilin treatment. The median age was 12 years (range 7 months to 76 years) and 46% were male. The dosage of Biocilin was determined by the category of neutropenia. Initial dosage of Biocilin:


The dosage was increased incrementally to 12 mcg/kg/day divided 2 times per day if there was no response.

Adverse reactions with ≥ 5% higher incidence in Biocilin patients compared to patients receiving no Biocilin included arthralgia, bone pain, back pain, muscle spasms, musculoskeletal pain, pain in extremity, splenomegaly, anemia, upper respiratory tract infection, and urinary tract infection (upper respiratory tract infection and urinary tract infection were higher in the Biocilin arm, total infection related events were lower in Biocilin treated patients), epistaxis, chest pain, diarrhea, hypoesthesia, and alopecia.

6.2 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Biocilin has not been adequately determined. While available data suggest that a small proportion of patients developed binding antibodies to Biocilin, the nature and specificity of these antibodies has not been adequately studied. In clinical studies using Biocilin, the incidence of antibodies binding to filgrastim was 3%. 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 filgrastim 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.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Biocilin. 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. The potential risk to the fetus is unknown. Reports in the scientific literature have described transplacental passage of Biocilin in pregnant women when administered ≤ 30 hours prior to preterm delivery (≤ 30 weeks gestation). Biocilin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Effects of Biocilin on prenatal development have been studied in rats and rabbits. No malformations were observed in either species. Biocilin has been shown to have adverse effects in pregnant rabbits at doses 2 to 10 times higher than the human doses. In pregnant rabbits showing signs of maternal toxicity, reduced embryo-fetal survival (at 20 and 80 mcg/kg/day) and increased abortions (at 80 mcg/kg/day) were observed. In pregnant rats, no maternal or fetal effects were observed at doses up to 575 mcg/kg/day.

Offspring of rats administered Biocilin during the peri-natal and lactation periods exhibited a delay in external differentiation and growth retardation (≥ 20 mcg/kg/day) and slightly reduced survival rate (100 mcg/kg/day).

8.3 Nursing Mothers

It is not known whether Biocilin is excreted in human milk. Because many drugs are excreted in human milk‚ caution should be exercised if Biocilin is administered to women who are breastfeeding.

8.4 Pediatric Use

In patients with cancer receiving myelosuppressive chemotherapy‚ 15 pediatric patients median age 2.6 years with neuroblastoma were treated with myelosuppressive chemotherapy (cyclophosphamide‚ cisplatin‚ doxorubicin‚ and etoposide) followed by subcutaneous Biocilin at doses of 5, 10, or 15 mcg/kg/day for 10 days (n = 5/dose) (Study 8). The pharmacokinetics of Biocilin in pediatric patients after chemotherapy are similar to those in adults receiving the same weight-normalized doses, suggesting no age-related differences in the pharmacokinetics of Biocilin. In this population‚ Biocilin was well tolerated. There was one report of palpable splenomegaly and one report of hepatosplenomegaly associated with Biocilin therapy; however‚ the only consistently reported adverse event was musculoskeletal pain‚ which is no different from the experience in the adult population.

The safety and effectiveness of Biocilin have been established in pediatric patients with SCN [see Clinical Studies ( 14.5 )]. In a phase 3 study (Study 7) to assess the safety and efficacy of Biocilin in the treatment of SCN, 123 patients with a median age of 12 years (range 7 months to 76 years) were studied. Of the 123 patients, 12 were infants (7 months to 2 years of age), 49 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 731 patients in the surveillance study, 429 were pediatric patients < 18 years of age (range 0.9 to 17) [see Indications and Usage ( 1.5 ), Dosage and Administration ( 2.6 ), and Clinical Studies ( 14.5 )].

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 Biocilin 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.

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 Biocilin treatment. The relationship of these events to Biocilin administration is unknown [see Warnings and Precautions ( 5.8 ) and Adverse Reactions ( 6 )].

The use of Biocilin to increase survival in pediatric patients acutely exposed to myelosuppressive doses of radiation is based on studies conducted in animals and clinical data supporting the use of Biocilin in other approved indications [see Dosage and Administration ( 2.1 to 2.4 ) and Clinical Studies ( 14.6 )].

8.5 Geriatric Use

Among 855 subjects enrolled in 3 randomized, placebo-controlled trials of NEUPOGEN-treated patients receiving 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.

Clinical studies of Biocilin in other approved indications (i.e., BMT 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.

10 OVERDOSAGE

The maximum tolerated dose of NEUPOGEN has not been determined. In Biocilin clinical trials of patients with cancer receiving myelosuppressive chemotherapy‚ WBC counts > 100‚000/mm3 have been reported in less than 5% of patients‚ but were not associated with any reported adverse clinical effects. 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.

11 DESCRIPTION

Biocilin (filgrastim) is a 175 amino acid human granulocyte colony-stimulating factor (G-CSF) manufactured by recombinant DNA technology. Biocilin is produced by Escherichia coli (E coli) bacteria into which has been inserted the human granulocyte colony-stimulating factor gene. Biocilin 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 E coli. Because Biocilin is produced in E coli‚ the product is non-glycosylated and thus differs from G-CSF isolated from a human cell.

Biocilin injection is a sterile‚ clear‚ colorless‚ preservative-free liquid containing Biocilin at a specific activity of 1.0 ± 0.6 x 108 U/mg (as measured by a cell mitogenesis assay). The product is available in single-dose vials and prefilled syringes. The single-dose vials contain either 300 mcg/mL or 480 mcg/1.6 mL of Biocilin. The single-dose prefilled syringes contain either 300 mcg/0.5 mL or 480 mcg/0.8 mL of Biocilin. See table below for product composition of each single-dose vial or prefilled syringe.

300 mcg/mL Vial 480 mcg/1.6 mL Vial 300 mcg/0.5 mL Syringe 480 mcg/0.8 mL Syringe
Biocilin 300 mcg 480 mcg 300 mcg 480 mcg
acetate 0.59 mg 0.94 mg 0.295 mg 0.472 mg
polysorbate 80 0.04 mg 0.064 mg 0.02 mg 0.032 mg
sodium 0.035 mg 0.056 mg 0.0175 mg 0.028 mg
sorbitol 50 mg 80 mg 25 mg 40 mg
water for Injection
USP q.s. ad* 1 mL 1.6 mL 0.5 mL 0.8 mL

* quantity sufficient to make

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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 that 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 functions. G-CSF is not species-specific and has been shown to have minimal direct in vivo or in vitro effects on the production or activity of hematopoietic cell types other than the neutrophil lineage.

12.2 Pharmacodynamics

In phase 1 studies involving 96 patients with various nonmyeloid malignancies‚ Biocilin 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 Biocilin was administered intravenous (1 to 70 mcg/kg twice daily)‚ subcutaneous (1 to 3 mcg/kg once daily)‚ or by continuous subcutaneous infusion (3 to 11 mcg/kg/day). With discontinuation of Biocilin 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 Biocilin; however‚ the percentage of monocytes in the differential count remained within the normal range. Absolute counts of both eosinophils and basophils did not change and were within the normal range following administration of Biocilin. Increases in lymphocyte counts following Biocilin administration have been reported in some normal subjects and patients with cancer.

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.

12.3 Pharmacokinetics

Biocilin exhibits nonlinear pharmacokinetics. Clearance is dependent on Biocilin concentration and neutrophil count: G-CSF receptor-mediated clearance is saturated by high concentration of Biocilin and is diminished by neutropenia. In addition, filgrastim is cleared by the kidney.

Subcutaneous administration of 3.45 mcg/kg and 11.5 mcg/kg of filgrastim resulted in maximum serum concentrations of 4 and 49 ng/mL‚ respectively‚ within 2 to 8 hours. After intravenous administration, the volume of distribution averaged 150 mL/kg and the elimination half-life was approximately 3.5 hours in both normal subjects and cancer subjects. Clearance rates of filgrastim were approximately 0.5 to 0.7 mL/minute/kg. Single parenteral doses or daily intravenous doses‚ over a 14-day period‚ resulted in comparable half-lives. The half-lives were similar for intravenous administration (231 minutes‚ following doses of 34.5 mcg/kg) and for subcutaneous administration (210 minutes‚ following Biocilin dosages of 3.45 mcg/kg). Continuous 24-hour intravenous infusions of 20 mcg/kg over an 11 to 20-day period produced steady-state serum concentrations of filgrastim with no evidence of drug accumulation over the time period investigated. The absolute bioavailability of filgrastim after subcutaneous administration is 60% to 70%.

Specific Populations

Patients Acutely Exposed to Myelosuppressive D oses of Radiation

The pharmacokinetics of Biocilin is not available in patients acutely exposed to myelosuppressive doses of radiation. Based on limited pharmacokinetics data in irradiated non-human primates, the area under the time-concentration curve (AUC), reflecting the exposure to Biocilin in non-human primates at 10 mcg/kg dose of Biocilin, appears to be similar to that in humans at 5 mcg/kg. Simulations conducted using the population pharmacokinetic model indicates that the exposures to Biocilin at a Biocilin dose of 10 mcg/kg in patients acutely exposed to myelosuppressive doses of radiation are expected to exceed the exposures at a dose of 10 mcg/kg in irradiated non-human primates.

Pediatric Patients

The pharmacokinetics of Biocilin in pediatric patients after chemotherapy are similar to those in adult patients receiving the same weight-normalized doses, suggesting no age-related differences in the pharmacokinetics of filgrastim [see Use in Specific Populations ( 8.4 )].

Renal Impairment

In a study with healthy volunteers, subjects with moderate renal impairment, and subjects with end-stage renal disease (n = 4 per group), higher serum concentrations were observed in subjects with end-stage renal disease. However, dose adjustment in patients with renal impairment is not necessary.

Hepatic Impairment

Pharmacokinetics and pharmacodynamics of Biocilin are similar between subjects with hepatic impairment and healthy subjects (n = 12/group). The study included 10 subjects with mild hepatic impairment (Child-Pugh Class A) and 2 subjects with moderate hepatic impairment (Child-Pugh Class B). Therefore, Biocilin dose adjustment for patients with hepatic impairment is not necessary.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

13.2 Animal Toxicology and Pharmacology

Biocilin was administered to monkeys‚ dogs‚ hamsters‚ rats‚ and mice as part of a nonclinical toxicology program, which included studies up to 1 year duration.

In the repeated-dose studies‚ changes observed were attributable to the expected pharmacological actions of Biocilin (i.e.‚ dose-dependent increases in white blood cell counts‚ increased circulating segmented neutrophils‚ and increased myeloid:erythroid ratio in bone marrow). Histopathologic examination of the liver and spleen revealed evidence of ongoing extramedullary granulopoiesis, and dose-related increases in spleen weight were seen in all species. These changes all reversed after discontinuation of treatment.

14 CLINICAL STUDIES

14.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy

The safety and efficacy of Biocilin to decrease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs were established in a randomized‚ double-blind‚ placebo-controlled trial conducted in patients with small cell lung cancer.

In Study 1, patients received up to 6 cycles of intravenous chemotherapy including intravenous cyclophosphamide and doxorubicin on day 1; and etoposide on days 1, 2, and 3 of 21 day cycles. Patients were randomized to receive Biocilin (n = 99) at a dose of 230 mcg/m2 (4 to 8 mcg/kg/day) or placebo (n = 111). Study drug was administered subcutaneously daily beginning on day 4, for a maximum of 14 days. A total of 210 patients were evaluable for efficacy and 207 were evaluable for safety. The demographic and disease characteristics were balanced between arms with a median age of 62 (range 31 to 80) years; 64% males; 89% Caucasian; 72% extensive disease and 28% limited disease.

The main efficacy endpoint was the incidence of febrile neutropenia. Febrile neutropenia was defined as an ANC < 1000/mm3 and temperature > 38.2°C. Treatment with Biocilin resulted in a clinically and statistically significant reduction in the incidence of infection‚ as manifested by febrile neutropenia, 40% for NEUPOGEN-treated patients and 76% for placebo-treated patients (p < 0.001). There were also statistically significant reductions in the incidence and overall duration of infection manifested by febrile neutropenia; the incidence, severity and duration of severe neutropenia (ANC < 500/mm3); the incidence and overall duration of hospital admissions; and the number of reported days of antibiotic use.

14.2 Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy

The safety and efficacy of Biocilin to reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML) was established in a randomized, double-blind‚ placebo-controlled‚ multi-center trial in patients with newly diagnosed, de novo AML (Study 4).

In Study 4 the initial induction therapy consisted of intravenous daunorubicin days 1, 2, and 3; cytosine arabinoside days 1 to 7; and etoposide days 1 to 5. Patients were randomized to receive subcutaneous Biocilin (n = 259) at a dose of 5 mcg/kg/day or placebo (n = 262) from 24 hours after the last dose of chemotherapy until neutrophil recovery (ANC ≥ 1000/mm3 for 3 consecutive days or ≥ 10,000/mm3 for 1 day) or for a maximum of 35 days. The demographic and disease characteristics were balanced between arms with a median age of 54 (range 16 to 89) years; 54% males; initial white blood cell count (65% < 25,000/mm3 and 27% > 100,000/mm3); 29% unfavorable cytogenetics.

The main efficacy endpoint was median duration of severe neutropenia defined as neutrophil count < 500/mm3. Treatment with Biocilin resulted in a clinically and statistically significant reduction in median number of days of severe neutropenia, NEUPOGEN-treated patients 14 days, placebo-treated patients 19 days (p = 0.0001: difference of 5 days (95% CI: -6.0, -4.0)). There was a reduction in the median duration of intravenous antibiotic use, NEUPOGEN-treated patients: 15 days versus placebo-treated patients: 18.5 days; a reduction in the median duration of hospitalization, NEUPOGEN-treated patients: 20 days versus placebo-treated patients: 25 days.

There were no statistically significant differences between the Biocilin and the placebo groups in complete remission rate (69% - Biocilin, 68% - placebo), median time to progression of all randomized patients (165 days - Biocilin, 186 days - placebo), or median overall survival (380 days - Biocilin, 425 days - placebo).

14.3 Patients with Cancer Undergoing Bone Marrow Transplantation

The safety and efficacy of Biocilin to reduce the duration of neutropenia in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by autologous bone marrow transplantation was evaluated in 2 randomized controlled trials of patients with lymphoma. The safety and efficacy of Biocilin to reduce the duration of neutropenia in patients undergoing myeloablative chemotherapy followed by allogeneic bone marrow transplantation was evaluated in a randomized placebo controlled trial (Study 10).

In Study 6 patients with Hodgkin’s disease received a preparative regimen of intravenous cyclophosphamide, etoposide, and BCNU (“CVP”), and patients with non-Hodgkin’s lymphoma received intravenous BCNU, etoposide, cytosine arabinoside and melphalan (“BEAM”). There were 54 patients randomized 1:1:1 to control, Biocilin 10 mcg/kg/day, and Biocilin 30 mcg/kg/day as a 24 hour continuous infusion starting 24 hours after bone marrow infusion for a maximum of 28 days. The median age was 33 (range 17 to 57) years; 56% males; 69% Hodgkin’s disease and 31% non-Hodgkin’s lymphoma.

The main efficacy endpoint was duration of severe neutropenia ANC < 500/mm3. A statistically significant reduction in the median number of days of severe neutropenia (ANC < 500/mm3) occurred in the NEUPOGEN-treated groups versus the control group (23 days in the control group‚ 11 days in the 10 mcg/kg/day group, and 14 days in the 30 mcg/kg/day group [11 days in the combined treatment groups‚ p = 0.004]).

In Study 9, patients with Hodgkin’s disease and non-Hodgkin’s lymphoma received a preparative regimen of intravenous cyclophosphamide, etoposide, and BCNU (“CVP”). There were 43 evaluable patients randomized to continuous subcutaneous infusion Biocilin 10 mcg/kg/day (n = 19), Biocilin 30 mcg/kg/day (n = 10) and no treatment (n = 14) starting the day after marrow infusion for a maximum of 28 days. The median age was 33 (range 17 to 56) years; 67% males; 28% Hodgkin’s disease and 72% non-Hodgkin’s lymphoma.

The main efficacy endpoint was duration of severe neutropenia. There was statistically significant reduction in the median number of days of severe neutropenia (ANC < 500/mm3) in the NEUPOGEN-treated groups versus the control group (21.5 days in the control group versus 10 days in the NEUPOGEN-treated groups, p < 0.001). The number of days of febrile neutropenia was also reduced significantly in this study (13.5 days in the control group versus 5 days in the NEUPOGEN-treated groups‚ p < 0.0001).

In Study 10, 70 patients scheduled to undergo bone marrow transplantation for multiple underlying conditions using multiple preparative regimens were randomized to receive Biocilin 300 mcg/m2/day (n = 33) or placebo (n = 37) days 5 through 28 after marrow infusion. The median age was 18 (range 1 to 45) years, 56% males. The underlying disease was: 67% hematologic malignancy, 24% aplastic anemia, 9% other. A statistically significant reduction in the median number of days of severe neutropenia occurred in the treated group versus the control group (19 days in the control group and 15 days in the treatment group‚ p < 0.001) and time to recovery of ANC to ≥ 500/mm3 (21 days in the control group and 16 days in the treatment group‚ p < 0.001).

14.4 Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy

The safety and efficacy of Biocilin to mobilize autologous peripheral blood progenitor cells for collection by leukapheresis was supported by the experience in uncontrolled trials, and a randomized trial comparing hematopoietic stem cell rescue using Biocilin mobilized autologous peripheral blood progenitor cells to autologous bone marrow (Study 11). Patients in all these trials underwent a similar mobilization/collection regimen: Biocilin was administered for 6 to 7 days‚ in most cases the apheresis procedure occurred on days 5‚ 6, and 7. The dose of Biocilin ranged between 10 to 24 mcg/kg/day and was administered subcutaneously by injection or continuous intravenous infusion.

Engraftment was evaluated in 64 patients who underwent transplantation using Biocilin mobilized autologous hematopoietic progenitor cells in uncontrolled trials. Two of the 64 patients (3%) did not achieve the criteria for engraftment as defined by a platelet count ≥ 20‚000/mm3 by day 28. In clinical trials of Biocilin for the mobilization of hematopoietic progenitor cells‚ Biocilin was administered to patients at doses between 5 to 24 mcg/kg/day after reinfusion of the collected cells until a sustainable ANC (≥ 500/mm3) was reached. The rate of engraftment of these cells in the absence of Biocilin post transplantation has not been studied.

Study 11 was a randomized, unblinded study of patients with Hodgkin’s disease or non-Hodgkin’s lymphoma undergoing myeloablative chemotherapy‚ 27 patients received NEUPOGEN-mobilized autologous hematopoietic progenitor cells and 31 patients received autologous bone marrow. The preparative regimen was intravenous BCNU, etoposide, cytosine arabinoside and melphalan (“BEAM”). Patients received daily Biocilin 24 hours after stem cell infusion at a dose of 5 mcg/kg/day. The median age was 33 (range 1 to 59) years; 64% males; 57% Hodgkin’s disease and 43% non-Hodgkin’s lymphoma. The main efficacy endpoint was number of days of platelet transfusions. Patients randomized to NEUPOGEN-mobilized autologous peripheral blood progenitor cells compared to autologous bone marrow had significantly fewer days of platelet transfusions (median 6 vs 10 days).

14.5 Patients with Severe Chronic Neutropenia

The safety and efficacy of Biocilin to reduce the incidence and duration of sequelae of neutropenia in symptomatic adult and pediatric patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia was established in a randomized controlled trial conducted in patients with severe neutropenia (Study 7).

Patients eligible for Study 7 had a history of severe chronic neutropenia documented with an ANC < 500/mm3 on three occasions during a 6 month period, or in patients with cyclic neutropenia 5 consecutive days of ANC < 500/mm3 per cycle. In addition patients must have experienced a clinically significant infection during the previous 12 months. Patients were randomized to a 4 month observation period followed by Biocilin treatment or immediate Biocilin treatment. The median age was 12 years (range 7 months to 76 years); 46% males; 34% idiopathic, 17% cyclic and 49% congenital neutropenia.

Biocilin was administered subcutaneously. The dose of Biocilin was determined by the category of neutropenia. Initial dose of Biocilin:


The dose was increased incrementally to 12 mcg/kg/day divided 2 times per day if there was no response.

The main efficacy endpoint was response to Biocilin treatment. ANC response from baseline (< 500/mm3) was defined as follows:


There were 112 of 123 patients who demonstrated a complete or partial response to Biocilin treatment.

Additional efficacy endpoints included a comparison between patients randomized to 4 months of observation and patients receiving Biocilin of the following parameters:


The incidence for each of these 5 clinical parameters was lower in the Biocilin arm compared to the control arm for cohorts in each of the 3 major diagnostic categories. An analysis of variance showed no significant interaction between treatment and diagnosis‚ suggesting that efficacy did not differ substantially in the different diseases. Although Biocilin substantially reduced neutropenia in all patient groups‚ in patients with cyclic neutropenia‚ cycling persisted but the period of neutropenia was shortened to 1 day.

14.6 Patients Acutely Exposed to Myelosuppressive Doses of Radiation (Hematopoietic Syndrome of Acute Radiation Syndrome)

Efficacy studies of Biocilin could not be conducted in humans with acute radiation syndrome for ethical and feasibility reasons. Approval of this indication was based on efficacy studies conducted in animals and data supporting the use of Biocilin for other approved indications [see Dosage and Administration ( 2.1 to 2.4 )].

Because of the uncertainty associated with extrapolating animal efficacy data to humans, the selection of human dose for NEUPOGEN is aimed at providing exposures to Biocilin that exceed those observed in animal efficacy studies. The 10 mcg/kg daily dose is selected for humans exposed to myelosuppressive doses of radiation because the exposure associated with such a dose is expected to exceed the exposure associated with a 10 mcg/kg dose in non-human primates [see Pharmacokinetics ( 12.3 )]. The safety of Biocilin at a daily dose of 10 mcg/kg has been assessed on the basis of clinical experience in approved indications.

The efficacy of Biocilin was studied in a randomized, blinded, placebo-controlled study in a non-human primate model of radiation injury. The planned sample size was 62 animals, but the study was stopped at the interim analysis with 46 animals because efficacy was established. Rhesus macaques were randomized to a control (n = 22) or treated (n = 24) group. Animals were exposed to total body irradiation of 7.4 ± 0.15 Gy delivered at 0.8 ± 0.03 Gy/min, representing a dose that would be lethal in 50% of animals by 60 days of follow-up (LD50/60). Starting on day 1 after irradiation, animals received daily subcutaneous injections of placebo (5% dextrose in water) or Biocilin (10 mcg/kg/day). Blinded treatment was stopped when one of the following criteria was met: ANC ≥ 1,000/mm3 for 3 consecutive days, or ANC ≥ 10,000/mm3 for more than 2 consecutive days within study day 1 to 5, or ANC ≥ 10,000/mm3 any time after study day 5. Animals received medical management consisting of intravenous fluids, antibiotics, blood transfusions, and other support as required.

Biocilin significantly (at 0.023 level of significance) reduced 60-day mortality in the irradiated non-human primates: 21% mortality (5/24) in the Biocilin group compared to 59% mortality (13/22) in the control group.

1 6 HOW SUPPLIED/STORAGE AND HANDLING

Vials

Single-dose‚ preservative-free vials containing 300 mcg/mL of Biocilin. Dispensing packs of 10 vials (NDC 55513-530-10).

Single-dose‚ preservative-free vials containing 480 mcg/1.6 mL (300 mcg/mL) of Biocilin. Dispensing packs of 10 vials (NDC 55513-546-10).

Prefilled Syringes (SingleJect ® )

Single-dose‚ preservative-free, prefilled syringe with 27 gauge, ½ inch needle with an UltraSafe® Needle Guard, containing 300 mcg/0.5 mL of Biocilin.


Single-dose‚ preservative-free, prefilled syringe with 27 gauge, ½ inch needle with an UltraSafe® Needle Guard, containing 480 mcg/0.8 mL of Biocilin.


The needle cap of the prefilled syringe contains dry natural rubber (a derivative of latex) [see Dosage and Adm i nistration ( 2.6 ) ].

Store Biocilin at 2° to 8°C (36° to 46°F) in the carton to protect from light. Do not leave Biocilin in direct sunlight. Avoid freezing; if frozen, thaw in the refrigerator before administration. Discard Biocilin if frozen more than once. Avoid shaking. Transport via a pneumatic tube has not been studied.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Review the steps for direct patient administration with patients and caregivers. Training by the healthcare provider should aim to ensure that patients and caregivers can successfully perform all of the steps in the Instructions for Use of NEUPOGEN vial and prefilled syringe, including showing the patient or caregiver how to measure the required dose, particularly if a patient is on a dose other than the entire prefilled syringe. If a patient or caregiver is not able to demonstrate that they can measure the dose and administer the product successfully, you should consider whether the patient is an appropriate candidate for self-administration of NEUPOGEN or whether the patient would benefit from a different NEUPOGEN presentation.

Advise patients of the following risks and potential risks with Biocilin:


Instruct patients who self-administer Biocilin using the prefilled syringe or single-dose vial of the:


Biocilin® (filgrastim)

Manufactured by:

Amgen Inc.

One Amgen Center Drive

Thousand Oaks, California 91320-1799

U.S. License Number 1080

Patent: http://pat.amgen.com/neupogen/

© 1991-2016 Amgen Inc. All rights reserved.

www. NEUPOGEN.com

1-800-77-AMGEN (1-800-772-6436)

1xxxxxx

v30

Patient Information

Biocilin ® (nu-po-jen)

(filgrastim )

injection

What is Biocilin?

Biocilin is a man-made form of granulocyte colony-stimulating factor (G-CSF). G-CSF is a substance produced by the body. It stimulates the growth of neutrophils, a type of white blood cell important in the body’s fight against infection.

Acute Radiation Syndrome: The effectiveness of Biocilin for this use was only studied in animals, because it could not be studied in people.

Do not take Biocilin if you have had a serious allergic reaction to human G-CSFs such as Biocilin or pegfilgrastim products.
Before you take Biocilin, tell your healthcare provider about all of your medical conditions, including if you:

  • have a sickle cell disorder.

  • have kidney problems.

  • are receiving radiation therapy.

  • are allergic to latex. The needle cap on the prefilled syringe contains dry natural rubber (derived from latex). You should not give Biocilin using the prefilled syringe if you have latex allergies. Ask your healthcare provider about using the vial if you have latex allergies.

  • are pregnant or plan to become pregnant. It is not known if Biocilin will harm your unborn baby.

  • are breastfeeding or plan to breastfeed. It is not known if Biocilin passes into your breast milk.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How will I receive Biocilin?
  • Biocilin injections can be given by a healthcare provider by intravenous (IV) infusion or under your skin (subcutaneous injection). Your healthcare provider may decide subcutaneous injections can be given at home by you or your caregiver. If Biocilin is given at home, see the detailed “Instructions for Use” that comes with your Biocilin for information on how to prepare and inject a dose of Biocilin.

  • You and your caregiver should be shown how to prepare and inject Biocilin before you use it, by your healthcare provider.

  • Your healthcare provider will tell you how much Biocilin to inject and when to inject it. Do not change your dose or stop Biocilin unless your healthcare provider tells you to.

  • If you are receiving Biocilin because you are also receiving chemotherapy, your dose of Biocilin should be injected at least 24 hours before or 24 hours after your dose of chemotherapy.

  • If you miss a dose of Biocilin, talk to your healthcare provider about when you should give your next dose.
What are the possible side effects of Biocilin?

Biocilin may cause serious side effects, including:

  • Spleen rupture. Your spleen may become enlarged and can rupture. A ruptured spleen can cause death. Call your healthcare provider right away if you have pain in the left upper stomach (abdomen) area or your left shoulder.

  • A serious lung problem called acute respiratory distress syndrome (ARDS). Call your healthcare provider or get emergency medical help right away if you have shortness of breath with or without a fever, trouble breathing, or a fast rate of breathing.

  • Serious allergic reactions. Biocilin can cause serious allergic reactions. These reactions can cause a rash over your whole body, shortness of breath, wheezing, dizziness, swelling around your mouth or eyes, fast heart rate, and sweating. If you have any of these symptoms, stop using Biocilin and call your healthcare provider or get emergency medical help right away.

  • Sickle cell crises. You may have a serious sickle cell crisis if you have a sickle cell disorder and receive Biocilin. Serious sickle cell crises have happened in people with sickle cell disorders receiving Biocilin that has sometimes led to death. Call your healthcare provider right away if you have symptoms of sickle cell crisis such as pain or difficulty breathing.

  • Kidney injury (glomerulonephritis). Biocilin can cause kidney injury. Call your healthcare provider right away if you develop any of the following symptoms:

    ○ swelling of your face or ankles

    ○ blood in your urine or dark colored urine

    ○ you urinate less than usual

  • Capillary leak syndrome. Biocilin can cause fluid to leak from blood vessels into your body’s tissues. This condition is called “Capillary Leak Syndrome” (CLS). CLS can quickly cause you to have symptoms that may become life-threatening. Get emergency medical help right away if you develop any of the following symptoms:

    ○ swelling or puffiness and are urinating less than usual

    ○ trouble breathing

    ○ swelling of your stomach-area (abdomen) and feeling of fullness

    ○ dizziness or feeling faint

    ○ a general feeling of tiredness

  • Decreased platelet count (thrombocytopenia). Your healthcare provider will check your blood during treatment with Biocilin. Tell your healthcare provider if you have unusual bleeding or bruising during treatment with Biocilin. This could be a sign of decreased platelet counts, which may reduce the ability of your blood to clot.

  • Increased white blood cell count (leukocytosis). Your healthcare provider will check your blood during treatment with Biocilin.

  • Inflammation of your blood vessels (cutaneous vasculitis). Tell your healthcare provider if you develop purple spots or redness of your skin.
The most common side effects of Biocilin include aching in the bones and muscles.

These are not all the possible side effects of Biocilin. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Biocilin?

  • Store Biocilin in the refrigerator between 36˚F to 46˚F (2˚C to 8˚C).

  • Do not freeze.

  • Keep Biocilin in the original carton to protect from light or physical damage.

  • Do not shake Biocilin.

  • Take Biocilin out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection.

  • Throw away (dispose of) any Biocilin that has been left at room temperature for longer than 24 hours.

  • After you inject your dose, throw away (dispose of) any unused Biocilin left in the vials or prefilled syringes. Do not save unused Biocilin in the vials or prefilled syringes for later use.
Keep Biocilin out of the reach of children.
General information about the safe and effective use of Biocilin.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Biocilin for a condition for which it was not prescribed. Do not give Biocilin to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Biocilin that is written for healthcare professionals.

What are the ingredients in Biocilin?

Active ingredient: Biocilin

Inactive ingredients: acetate, polysorbate 80, sodium, sorbitol, and water for Injection

Biocilin® (filgrastim)

Manufactured by: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799 U.S.A.

US License No. 1080 1xxxxxx © 1991-2016 Amgen Inc. All rights reserved. v15


This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: June 2016

Instructions for Use

Biocilin ® (nu-po-jen)

(filgrastim )

Injection

Single-Dose Prefilled Syringe

Guide to parts

Before use

After use



Important: The needle is covered by the gray needle cap before use.

Important

Read the Patient Information for important information you need to know about Biocilin before using these Instructions for Use.

Before you use a Biocilin prefilled syringe, read this important information .

Storing your prefilled syringe


Using your prefilled syringe


Call your healthcare provider if you have any questions.

Step 1: Prepare

A Remove the prefilled syringe carton from the refrigerator.

Put the original carton with any unused prefilled syringes back in the refrigerator.

Remove the syringe tray from the carton. On a clean, well-lit surface, place the syringe tray at room temperature for 30 minutes before you give an injection.


Open the tray by peeling away the cover. Grab the orange safety guard to remove the prefilled syringe from the tray.

For safety reasons:


B Inspect the medicine and prefilled syringe.

Turn the prefilled syringe so you can see the medicine window and markings. Make sure the medicine in the prefilled syringe is clear and colorless.


C Gather all materials needed for your injection.

Wash your hands thoroughly with soap and water.

On a clean, well-lit work surface, place the:



Step 2: Get ready

D Prepare and clean your injection site.

You can use:


Clean your injection site with an alcohol wipe.


If you want to use the same injection site, make sure it is not the same spot on the injection site area you used for a previous injection.


E Hold the prefilled syringe by the syringe barrel. Carefully pull the gray needle cap straight off and away from your body.



Important: Throw the gray needle cap into the sharps disposal container.

F

Your healthcare provider has prescribed either a “full” syringe dose or a “partial” syringe dose of Biocilin.

- If you are prescribed a full dose, you will inject all of the medicine from your prefilled syringe. For a full dose, go directly to Step 3 : Subcutaneous (under the skin) injection.

- If you are prescribed a partial dose of Biocilin, start with Step G below.

G Point the needle up and tap gently until the air rises to the top.


H Slowly push the plunger rod up to the line on the syringe barrel that matches your prescribed dose.




Important: Do not slide the orange safety guard over the needle before you give the injection. This will “activate” or lock the orange safety guard.

As you push the plunger rod up, air and extra medication is removed. Check to make sure the plunger lines up with the syringe markings for your prescribed dose. If you remove too much medicine, get a new prefilled syringe and start again at Step 1.


Step 3: Subcutaneous (under the skin) injection

I Pinch your injection site to create a firm surface.


Important: Keep skin pinched while injecting.

J Hold the pinch. Insert the needle into the skin at 45 to 90 degrees.


K Using slow and constant pressure, push the plunger rod until it reaches the bottom.


When done, gently pull the syringe off of your skin.


Important: When you remove the syringe, if it looks like the medicine is still in the syringe barrel, this means you have not received a full dose. Call your healthcare provider right away.

Step 4: Finish

L


For your safety, pull the orange safety guard until it clicks and covers the needle.

Once extended, the orange safety guard will lock into position and will not slide back over the needle.

Keep your hands away from the needle at all times.

M Discard (throw away) the used prefilled syringe.



Important: Always keep the sharps disposal container out of the reach of children.

N Examine the injection site.

If there is blood, press a cotton ball or gauze pad on your injection site. Do not rub the injection site. Apply an adhesive bandage if needed.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured by:

Amgen Inc.

One Amgen Center Drive

Thousand Oaks, California 91320-1799

U.S. License No. 1080

© 2016 All rights reserved.

1xxxxxx

Revised: 06/2016

v1

Guide to parts - Before use. Guide to parts - After use. Open the tray by peeling away the cover. Grab the orange safety guard to remove the prefilled syringe from the tray. Inspect the medicine and prefilled syringe. Prefilled syringe Alcohol wipe, Cotton ball or gauze pad, Adhesive bandage, Sharps disposal container Prepare and clean your injection site. Hold the prefilled syringe by the syringe barrel. Carefully pull the gray needle cap straight off and away from your body. Important: Throw the gray needle cap into the sharps disposal container. STOP Check your prescription before you inject your dose. Point the needle up and tap gently until the air rises to the top. Slowly push the plunger rod up to the line on the syringe barrel that matches your prescribed dose. As you push the plunger up, air and extra medication is removed, so you receive your prescribed dose. Pinch your injection site to create a firm surface. Hold the pinch. Insert the needle into the skin at 45 to 90 degrees. Using slow and constant pressure, push the plunger rod until it reaches the bottom. STOP Before you finish! For your safety, pull the orange safety guard until it clicks and covers the needle. Put the used prefilled syringe in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the prefilled syringe in your household trash.

Instructions for Use

Biocilin ® (nu-po-jen)

(filgrastim)

Injection

Single-Dose Vial

Important

Read the Patient Information for important information you need to know about Biocilin before using these Instructions for Use.

Before you use a Biocilin vial, read this important information:

Storing your Biocilin vial


Using your vial


Call your healthcare provider if you have any questions.

Step 1: Prepare

A Remove the vial from the refrigerator.

On a clean, well-lit surface, place the vial at room temperature for 30 minutes before you give an injection.


B Inspect the vial.

Make sure the medicine in the vial is clear and colorless.


C Gather all materials needed for your injection.

Wash your hands thoroughly with soap and water.

On a clean, well-lit work surface, place the:


Step 2: Get Ready

D Take the cap off the vial. Clean the rubber stopper with one alcohol wipe.


E Check the carton containing the syringe. If the carton has been opened or damaged, do not use that syringe. Dispose of (throw away) that syringe in the sharps disposal container.

F Hold the syringe by the barrel with the needle cap pointing up. Carefully pull the needle cap straight off and away from your body.


Pull back on the plunger and draw air into the syringe that is the same amount (mL) as the dose of Biocilin that your healthcare provider prescribed.

Important: Throw the needle cap into the sharps disposal container.

G Keep the vial on the flat working surface and insert the needle straight down through the rubber stopper. Do not insert the needle through the rubber stopper more than 1 time.

H Push the plunger down and inject all the air from the syringe into the vial of Biocilin.

I Keep the needle in the vial and turn the vial upside down. Make sure that the Biocilin liquid is covering the tip of the needle.

J Keep the vial upside down and slowly pull back on the plunger to fill the syringe barrel with Biocilin to the correct marking amount (mL) of medicine that matches the dose your healthcare provider prescribed.

K Keep the needle in the vial and check for air bubbles in the syringe. If there are air bubbles, gently tap the syringe barrel with your finger until the air bubbles rise to the top. Slowly push the plunger up to push the air bubbles out of the syringe.

L Keep the tip of the needle in the liquid and again pull the plunger back to the number on the syringe barrel that matches your dose. Check again for air bubbles. The air in the syringe will not hurt you, but too large an air bubble can reduce your dose of Biocilin. If there are still air bubbles, repeat the steps above to remove them.

M Check again to make sure that you have the correct dose in the syringe. It is important that you use the exact dose prescribed by your healthcare provider. Do not remove the needle from the vial. Lay the vial down on its side with the needle still in the vial.

Step 3: Select and Prepare the Injection Site

N Prepare and clean your injection site.

You can use:


Clean your injection site with a clean alcohol wipe.


Step 4: Subcutaneous (under the skin) injection

O Remove the prepared syringe and needle from the vial.

P Pinch your injection site to create a firm surface.


Important: Keep skin pinched while injecting.

Q Hold the pinch. Insert the needle into the skin at a 45 to 90 degree angle.

R Using slow and constant pressure, push the plunger until it reaches the bottom.

When done gently pull the syringe off of your skin.

Step 5: Finish

S Discard (throw away) the used syringe and vial.


Important: Always keep the sharps disposal container out of the reach of children.

T Examine the injection site.

If there is blood, press a cotton ball or gauze pad on your injection site. Do not rub the injection site. Apply an adhesive bandage if needed.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Biocilin® (filgrastim)

Manufactured by:

Amgen Inc.

One Amgen Center Drive

Thousand Oaks, California 91320-1799 U.S.A.

U.S. License No. 1080

Revised: 06/2016

1xxxxxx

© 1991-2016 Amgen Inc. All rights reserved.

v1

VialDisposable syringe and needle2 alcohol wipesCotton ball or gauze padAdhesive bandageSharps disposal container Take the cap off the vial. Clean the rubber stopper with one alcohol wipe. Hold the syringe by the barrel with the needle cap pointing up. Carefully pull the needle cap straight off and away from your body. Important: Throw the needle cap into the sharps disposal container. Push the plunger down and inject all the air from the syringe into the vial of Biocilin. Keep the needle in the vial and turn the vial upside down. Make sure that the Biocilin liquid is covering the tip of the needle. Keep the needle in the vial and check for air bubbles in the syringe. If there are air bubbles, gently tap the syringe barrel with your finger until the air bubbles rise to the top. Slowly push the plunger up to push the air bubbles out of the syringe. Prepare and clean your injection site. Hold the pinch. Insert the needle into the skin at a 45 to 90 degree angle. Using slow and constant pressure, push the plunger until it reaches the bottom. Put your used syringes, needles, and vials in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) needles, syringes and vials in your household trash.

Biocilin pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Biocilin available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Biocilin destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Biocilin Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Biocilin pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."NEUPOGEN (FILGRASTIM) INJECTION, SOLUTION [AMGEN INC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Biocilin?

Depending on the reaction of the Biocilin after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Biocilin not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Biocilin addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Biocilin, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Biocilin consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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