Summary Basis of Decision for Grastofil

 

Grastofil was filed as a Subsequent Entry Biologic (SEB) to the Canadian authorized product, Neupogen.

Three comparability pharmacokinetic/pharmacodynamic (PK/PD) studies in healthy volunteers and a non-comparability single arm safety study in patients with breast cancer were submitted for review.

A critical review was conducted based on the totality of the data submitted. A justification was made which suggests that Grastofil be qualified as an SEB to the Canadian marketed Neupogen based on the following:

• analytically high similarity and the same final formulation have been demonstrated between Grastofil and the reference product;
• mechanism of action of granulocyte‑colony stimulating factor (G-CSF) is understood;
• comparability of PK/PD parameters in healthy volunteers has been demonstrated between Grastofil and the reference product;
• safety profile of Grastofil is in general consistent with the reference product Neupogen.

Grastofil was filed as a Subsequent Entry Biologic (SEB) to the Canadian authorized product, Neupogen.

Three comparability pharmacokinetic/pharmacodynamic (PK/PD) studies in healthy volunteers and a non-comparability single arm safety study in patients with breast cancer were submitted for review.

A critical review was conducted based on the totality of the data submitted. A justification was made which suggests that Grastofil be qualified as an SEB to the Canadian marketed Neupogen based on the following:

• analytically high similarity and the same final formulation have been demonstrated between Grastofil and the reference product;
• mechanism of action of granulocyte colony stimulating factor (G-CSF) is understood;
• comparability of PK/PD parameters in healthy volunteers has been demonstrated between Grastofil and the reference product;
• safety profile of Grastofil is in general consistent with the reference product Neupogen.

In addition, based on the demonstrated linearity of the reference product with SC route of administration, and the clinical experience with the reference product with dose range used for  both IV and SC routes of administration cross all indications, doses and routes of administration for which the Canadian reference product are licensed could be considered to be granted to Grastofil with proper product labelling and adequate post market long term safety monitoring in large real world patient populations.

The safety profile of Grastofil is in general, consistent with the known safety profiles of the reference product Neupogen. No new significant safety signals have been observed in healthy volunteers or in breast cancer patients from Grastofil clinical studies. However, long term safety data and safety profile (such as immunogenicity) in different and large patient populations are not available.

Clinical Pharmacology

Filgrastim (the medicinal ingredient in Grastofil) is a human G-CSF produced by recombinant deoxyribonucleic acid (DNA) technology. Granulocyte colony stimulating factor regulates the production of white blood cells. Grastofil stimulates the blood system through the bone marrow to produce white blood cells. Grastofil is used to treat neutropenia, a condition where the body makes too few white blood cells. Neutropenia may be a long‑standing condition where your body does not make enough white blood cells, or it may be caused by drugs used to treat cancer.

Pharmacokinetic/Pharmacodynamic Phase I Studies

Similarity of Grastofil (test product) to that of Neupogen (reference product) was assessed on the basis of the conventional 90% confidence intervals (CIs) for the test/reference ratio in the linear scale from the statistical analysis of the log-transformed area under the concentration‑time curve (AUC_T) and maximum plasma concentration (C_max) parameters for pharmacokinetic (PK).

The first study, KWI-300-101, purported to show biosimilarity between the European reference Neupogen and the test product at a dose of 5 µg/kg body weight, administered by intravenous (IV) infusion. However, when the dose is infused by IV, the rationale for biocomparability depends solely on a mechanical process which does not reflect any biological or chemical properties of the drug or formulation. The second study, KWI‑300-102, administered the dose by subcutaneous (SC) injection, with two cohorts, each at a fixed dose of either 75 µg or 150 µg. Administration via the SC route involves an in vivo absorption process which would reflect the drug’s biological and chemical properties and places any comparability with the reference drug on firmer theoretical grounds. The third study, KWI-300-103, also used the SC route and compared the test and reference products with daily SC injections over a four day period, in the context of a bioequivalence trial.

The comparability between Grastofil and the reference product was demonstrated. Pharmacokinetic parameters (plasma AUC_T, C_max, and terminal half-life [T_1/2]) were comparable between Grastofil and the reference product with single or repeat dose SC administration as shown in the Table 1 below, taken from the Grastofil Product Monograph.

Table 1: Pharmacokinetic Parameters, Mean (Standard Deviation)

Single dose IV 5 µg/kg	Grastofil (n = 35)	Neupogen (n = 35)	Ratio of Geometric Meana(%)	90% CI (%)
a The ratio of geometric means is the ratio (Grastofil/Neupogen) of the inverse transformation of the least square means.
AUCT (min*ng/mL)	22,047 (4,060)	24,341 (4,530)	90.6	N/A
Cmax (ng/mL)	103 (15)	112 (16)	92.5	N/A
T1/2 (min)	410 (84)	388 (113)	N/A	N/A
Clearance (mL/min)	16.4 (4.1)	14.9 (3.7)	N/A	N/A
Volume of Distribution (mL)	9,875 (4,003)	8,575 (4,241)	N/A	N/A
Single dose cross-over SC 150 µg	Grastofil (n = 35)	Neupogen (n = 35)	Ratio of Geometric Mean (%)	90% CI (%)
AUCT (min*ng/mL)	3,276 (920)	3,415 (1,094)	96.8	91.0 – 103.0
Cmax (ng/mL)	7.72 (2.35)	8.35 (3.05)	94.6	N/A
T1/2 (min)	519 (154)	551 (197)	N/A	N/A
Four daily SC 5 µg/kg	Grastofil (n = 35)	Neupogen (n = 34)	Ratio of Geometric Mean (%)	90% CI (%)
AUCT (min*ng/mL)	11,735 (2,737)	11,839 (3,292)	100.2	90.3 – 111.1
Cmax (ng/mL)	25.9 (7.0)	25.5 (7.8)	102.2	N/A
T1/2 (min)	216 (48)	207 (39)	N/A	N/A

Absolute neutrophil count (ANC) as the relevant PD marker for the activity of G-CSF were found comparable between Grastofil and the reference product as shown in Table 2 below, taken from the Grastofil Product Monograph.

Table 2: Pharmacodynamic Parameters, Mean (Standard Deviation)

Single dose IV 5 µg/kg	Grastofil (n = 35)	Neupogen (n = 35)	Ratio of Geometric Mean(%)	95% CI (%)
ANC AUCT (cells × 109/L*min)	46,137 (8,608)	46,602 (9,322)	99.1	94.8 – 103.7
ANC Cmax (cells × 109/L)	19.0 (4.4)	19.3 (5.2)	99.5	92.5 - 107.1
Single dose cross-over SC 150 µg	Grastofil (n = 35)	Neupogen (n = 35)	Ratio of Geometric Mean (%)	95% CI (%)
ANC AUCT (cells × 109/L*min)	43,209 (7,922)	43,980 (6,866)	97.7	92.97 – 102.64
ANC Cmax (cells × 109/L)	19.0 (3.8)	19.6 (3.3)	96.3	91.02 – 101.93
Single dose cross-over SC 75 µg	Grastofil (n = 35)	Neupogen (n = 35)	Ratio of Geometric Mean (%)	95% CI (%)
ANC AUCT (cells × 109/L*min)	35,077 (6,526)	37,010 (7,623)	95.0	91.1 – 99.0
ANC Cmax (cells × 109/L)	17.1 (3.7)	18.6 (4.1)	92.0	87.1 – 97.1
Four daily SC 5 µg/kg all Day 1	Grastofil (n = 35)	Neupogen (n = 34)	Ratio of Geometric Mean (%)	95% CI (%)
ANC AUCT (cells × 109/L*min)	114,232 (19,346)	119,436 (20,700)	95.6	88.0 – 103.8
ANC Cmax (cells × 109/L)	30.5 (6.2)	32.3 (7.7)	95.2	85.8 – 105.6

Drug-Drug Interactions

No formal drug‑drug interaction studies were performed with Grastofil. Based on the information published for the reference product Neupogen, Grastofil must not be administered from 24 hours before to 24 hours after chemotherapy since concomitant chemotherapy administration may potentiate neutropenia. Lithium, which promotes the release of neutrophils, may potentiate the effects of Grastofil.

For further details, please refer to the Grastofil Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

Similarity between Grastofil and Neupogen (reference product) was demonstrated with equivalent trials based on three randomized comparative PK/PD Phase I studies (KWI‑300-101, KWI‑300‑102, and KWI‑300-103) previously described in the Clinical Pharmacology section above. In addition to these three PK/PD studies, safety of Grastofil was also assessed in a single-arm, multicenter, repeat dose, non‑comparative safety study (KWI-300-104) conducted in breast cancer patients.

KWI-300-104 was a single-arm, multicenter, repeat dose safety study of Grastofil (5 μg/kg/day, subcutaneous) in female patients, with stage IIA, IIB or IIIA breast cancer receiving taxotere adriamycin cyclophosphamide (TAC) chemotherapy (docetaxel 75 mg/m² IV, doxorubicin 50 mg/m² IV, and cyclophosphamide 500 mg/m² IV) known to induce neutropenia. The study consisted of three treatment periods: screening (up to 3 weeks), treatment period (6 cycles, 3 weeks between each treatment cycle) and safety follow-up period (up to 30 weeks following completion of TAC chemotherapy). During the treatment period, treatment with Grastofil began on day 2 of every chemotherapy cycle (at least 24 hours after chemotherapy) and was continued up to 14 days or until post-nadir absolute neutrophil count (ANC) recovery to normal or near-normal values by laboratory standards, whichever occurred first.

The patient population consisted of 120 Caucasian female patients with a mean age of 49.97 (Standard Deviation: 9.52) and range of 28 to 68 years , with stage IIA, IIB or IIIA breast cancer without neoadjuvant chemotherapy for this breast cancer. There were 39 (32.50%) patients at tumour stage IIA, 44 (36.67%) at stage IIB and 37 (30.83%) at stage IIIA. All patients were chemotherapy naïve and 22 (18.3%) patients had prior radiotherapy. The mean body weight was 71.1 kg), mean body height was 163.4 cm and mean body mass index (BMI) was 26.7 kg/m²).

In study KWI-300-104, 120 subjects were dosed. Overall, 113 patients (94.17%) completed the treatment period, 109 (90.83%) completed the Safety Follow-up period and 11 patients (9.17%) prematurely discontinued the study.

Safety findings were in general consistent with what had been observed with the reference product. The most frequently reported adverse event (AE) was bone pain. Ten serious AEs reported during the treatment and follow-up periods were considered unrelated to Grastofil. Two patients died during the follow-up period due to brain metastases and disease progression. Among the 57 severe AEs considered possibly, probably and definitely related, there were 56 bone pain reports and one abnormal injection site reaction. There were no signs of immunogenicity either detected by the laboratory or by clinical observation. Less frequent, however potentially more serious reactions reported in clinical studies of filgrastim, such as splenic rupture, severe sickle cell crisis, respiratory distress syndrome and Sweet’s syndrome, were not reported in this study. However, the study was powered to detect adverse events occurring with a frequency of more than 3%, and was not powered to detect adverse events that occur with less frequency. 

Overall Analysis of Efficacy

The data provided in this submission supports the biosimilarity of Grastofil and Neupogen. Based on the data package provided, Grastofil was shown to be efficacious and is considered to have a positive benefit‑risk ratio, similar to that of Neupogen. For more information, refer to the Grastofil Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Grastofil was primarily evaluated based on a pooled analysis derived from the three comparative single‑centre Phase I studies in healthy volunteers and one non‑comparative multicentre study in patients with breast cancer previously described in the Clinical Pharmacology and Clinical Efficacy sections, respectively. Standard safety assessments within these studies included treatment emergent adverse events (TEAEs), laboratory parameters, physical examinations, and vital signs assessment.

Adverse Drug Reaction Overview

Pharmacokinetic/Pharmacodynamic Phase I Studies

Of the 144 subjects exposed to filgrastim across the three pharmacokinetic/ pharmacodynamic studies (KWI‑300-101, KWI‑300‑102, and KWI‑300-103), 75 (52.04%) experienced TEAEs, and 50 (34.72%) had at least one possibly drug-related TEAE. Six subjects (4.17%) experienced TEAEs of severe intensity, but no serious TEAEs occurred. No TEAEs resulted in withdrawal of study subjects and no deaths occurred. Most common TEAEs under Grastofil treatment were headache, back pain, and rhinitis. Incidence of severe TEAEs was numerically higher in the Grastofil arm (4.17%) versus (vs.) Neupogen (1.39%). Incidence of gastrointestinal TEAEs (diarrhea, abdominal pain and nausea) was numerically higher in the Grastofil arm. The incidence of  study drug‑related or possibly drug related TEAEs included back pain, fatigue, arthralgia, feeling hot, neck pain, bone pain, dyspnea, and pyrexia were found to be similar between Grastofil and Neupogen. It is noted that in the repeated dose study (Study KWI-300-103, 5 μg/kg/day SC for 4 days), incidence of back pain was numerically higher in the Grastofil arm than in the Neupogen arm (20% vs. 14.4%).

Clinical Study KWI‑300‑104 in Breast Cancer

There were 1,216 TEAEs reported during the course of the KWI‑300‑104 study, with 964 (79.28%) assessed as not related to filgrastim. The most frequently reported AE was bone pain, with a total of 267 events reported in 80 (66.67%) patients. It was described as mild in 105 (39.33%), moderate in 99 (37.08%) and severe in 63 (23.60%) cases. Nine patients reported 10 serious adverse events (SAEs). All 10 SAEs reported during the treatment and follow-up periods were considered unrelated to filgrastim. Two patients (1.67%) died during the follow-up period due to brain metastasis and disease progression. There were 99 severe AEs, 42 of which were considered not related, 5 possibly, 30 probably and 22 definitely related to filgrastim. Among the 57 severe AEs considered possibly, probably and definitely related, there were 56 bone pain reports and 1 abnormal injection site reaction (ISR).

Antibodies were detected on the screening antibody assay in 4 patients. None of the samples were confirmed as positive on the confirmatory assay. Neutralization assay was not performed as no positive samples were detected. No samples tested positive for anti‑GCSF antibodies on the confirmatory antibody assay. 

Less frequent, however potentially more serious reactions reported in clinical studies of filgrastim, such as splenic rupture, severe sickle cell crisis, respiratory distress syndrome and Sweet’s syndrome, were not reported in this study. Nevertheless, the study was powered to detect adverse events occurring with a frequency of more than 3%, and was not powered to detect adverse events that occur with less frequency.

There were 93 abnormal ECG findings in 48 (40.00%) patients over the course of the study. Two of the findings were assessed as clinically significant (supraventricular/ventricular extrasystoles and cardiomyopathy). Both of these findings were reported as clinically significant following completion of study treatment at week 20, and both were assessed as unrelated to the study drug. Prolongation of QTc interval above 500 msec was observed in 3 patients following filgrastim treatment, at cycle 4 (n = 1), week 20 (n = 1) and week 21 (n = 1).

Specific Safety Issues

Pharmacological class effects related to granulocyte colony stimulating factor (G-CSF) include spleen enlargement/splenic rupture, sickle cell crisis, acute respiratory distress syndrome (ARDS), and capillary leak syndrome (CLS).

Spleen Enlargement/Rupture

Rare cases of splenic rupture have been reported following the administration of filgrastim. In the healthy volunteer studies, no subject was reported to experience spleen enlargement or splenic rupture. In the breast cancer study with Grastofil, one patient did report spleen pain in his patient diary. However, according to the investigator, no clinical sign of splenomegaly could be detected after physical examination or in the computed tomography (CT) scan performed few months later. Yet, splenic ruptures, including fatal cases have been reported following the administration of filgrastim. Therefore, a Black Box Warning identifying this risk has been included under the Serious Warnings and Precautions section of the Grastofil Product Monograph. Patients receiving Grastofil who report left upper abdominal and/or shoulder tip pain should be evaluated for an enlarged spleen or splenic rupture.

Sickle Cell Disorders

Severe sickle cell crisis, in some cases resulting in death, have been associated with the administration of filgrastim in patients with sickle cell disorders. Given this risk, a Black Box Warning has also been included under the Serious Warnings and Precautions section of the Grastofil Product Monograph to highlight this risk. In addition, only physicians qualified by specialized training or experience in the treatment of patients with sickle cell trait and sickle cell disease should prescribe Grastofil for such patients, and only after careful consideration of the potential risks and benefits.

Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) has been reported in patients receiving filgrastim and is postulated to be secondary to an influx of neutrophils to sites of inflammation in the lungs. Patients receiving Grastofil treatment who develop fever, lung infiltrates, or respiratory distress should be evaluated for the possibility of ARDS.

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

Capillary Leak Syndrome

Capillary Leak Syndrome (CLS) has been reported after the administration of filgrastim. Capillary Leak Syndrome may cause circulatory shock and may be fatal, and is characterized by hypotension, hypoalbuminemia, edema, and hemoconcentration. Episodes vary in frequency, severity, and maybe life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive treatment, which may include a need for intensive care.

Safety Issues of Interest

Simultaneous Use with Chemotherapy

The safety and efficacy of Grastofil given simultaneously with cytotoxic chemotherapy have not been established. Studies in adult patients showed that an interaction between concurrent filgrastim and 5-fluorouracil (5-FU) is possible and can result in a paradoxical fall in the absolute neutrophil count. Given the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, do not use Grastofil in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy.

The efficacy of Grastofil has not been evaluated in patients receiving chemotherapy associated with delayed myelosuppression (for example [e.g.] nitrosoureas) or with mitomycin C or with myelosuppressive doses of anti-metabolites such as fluorouracil (5‑FU) or cytosine arabinoside.

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

Carcinogenesis and Mutagenesis

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

Growth Factor Potential

 

 

Grastofil is a growth factor that primarily stimulates production of neutrophils. However, the possibility that Grastofil can act as a growth factor for certain tumor types cannot be excluded. Randomized studies have demonstrated that treatment with filgrastim following chemotherapy for acute myeloid leukemia does not adversely influence the outcome of treatment. The use of Grastofil in chronic myeloid leukemia (CML) and myelodysplasia (MDS) has not been fully investigated, and caution should be exercised in using this drug for patients with CML or MDS.

Tumor cells may be collected in the leukapheresis product, following peripheral blood progenitor collection (PBPC) mobilization by filgrastim. The clinical significance and the effect of reinfusion of tumor cells with the leukapheresis product are still unknown and the possible contribution of clonogenic tumor cells to an eventual relapse has not been determined.

Acute myeloid leukemia (AML) has been reported to occur in the natural history of severe chronic neutropenia without cytokine therapy. It is not known what, if any, additional risk may be imposed by Grastofil therapy.

Cardiovascular

Cardiac events (myocardial infarctions, arrhythmias) have been reported in 11 of 375 cancer patients receiving filgrastim in clinical studies, the relationship to Grastofil therapy is unknown. However, patients with pre-existing cardiac conditions receiving Grastofil should be monitored closely.

Hematologic

Leukocytosis

Cancer Patients Receiving Myelosuppressive Chemotherapy

White blood cell (WBC) counts of 100 × 10⁹/L or greater were observed in approximately 2% of patients at doses above 5 and up to 115 µg/kg/day in studies conducted with filgrastim. There were no reports of adverse events associated with this degree of leukocytosis. In order to avoid the potential complications of excessive leukocytosis, a complete blood count (CBC) is recommended twice per week during Grastofil therapy.

Cancer Patients Undergoing Peripheral Blood Progenitor (PBPC) Collection and Therapy

During the period of administration of Grastofil for PBPC mobilization in cancer patients, discontinuation of Grastofil is appropriate if the leukocyte count rises to >100 × 10⁹/L.

Thrombocytopenia

Thrombocytopenia has been reported in patients receiving filgrastim. Platelet counts should be monitored closely.

Hypersensitivity/ Allergic Reactions

Hypersensitivity, including serious allergic-type reactions and anaphylaxis occurring on initial or subsequent treatment have been reported in < 1 in 4,000 patients treated with filgrastim. These reactions generally involved at least two body systems, most often skin (rash, urticarial, facial edema), respiratory (wheezing, dyspnea), and cardiovascular (hypotension, tachycardia) events. Some reactions even occurred on initial exposure. Reactions usually arose within the first 30 minutes following administration and appeared to occur more frequently in patients receiving filgrastim intravenously. Rapid resolution of symptoms occurred in most cases after administration of antihistamines, steroids, bronchodilators, and/or epinephrine. Symptoms recurred in more than half the patients who were re‑challenged. Do not administer Grastofil to patients with a history of allergic reactions to filgrastim or pegfilgrastim.

Cutaneous Vasculitis

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

Immune

As with all therapeutic proteins, there is a potential for immunogenicity.

For the single arm safety study in breast cancer patients (KWI-300-104) with Grastofil, anti-drug antibodies were detected in the Screening antibody assay in 4 patients. None of the samples were confirmed as positive in the Confirmatory assay. In addition, there were no clinical manifestations of antibody formation, such as either hypersensitivity reactions or decreased ANC after completion of the treatment period.

The incidence of antibody development in patients receiving the reference product (Neupogen) has not been adequately determined. While available data suggest that a small proportion of patients developed binding antibodies to filgrastim, the nature and specificity of these antibodies has not been adequately studied. In clinical studies comparing filgrastim and pegfilgrastim, the incidence of antibodies binding to filgrastim was 3% (11/333). In these 11 patients, no evidence of neutralizing response was observed using a cell-based assay. 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 medication, 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. There is a theoretical possibility that an antibody directed against filgrastim may crossreact with endogenous G-CSF, resulting in immune-mediated neutropenia; however, this has not been reported in clinical studies or in post-marketing experience with filgrastim. Patients who develop hypersensitivity to filgrastim may have allergic or hypersensitivity reactions to other E.coli-derived proteins.

Other

Cancer Patients Receiving Myelosuppressive Chemotherapy

Premature Discontinuation of Filgrastim Therapy

A transient increase in neutrophil counts is typically seen 1-2 days after initiation of filgrastim therapy. However, for a sustained therapeutic response, Grastofil therapy should be continued following chemotherapy until the post nadir ANC reaches 10 × 10⁹/L. Therefore, the premature discontinuation of filgrastim therapy (that is [i.e.]), prior to the time of recovery from the expected neutrophil nadir, is generally not recommended.

Intensified doses of chemotherapeutic agents may lead to increased toxicities associated with these agents, including cardiac, pulmonary, neurologic, and dermatologic effects (please refer to the product monograph of the specific chemotherapy agents used). Increased exposure to alkylating agents particularly if combined with radiotherapy is known to be associated with the genesis of secondary malignancies. When considering chemotherapy dose intensification with Grastofil support, clinicians should weigh the risk of secondary malignancy against the potential benefits of improved primary disease outcome.

Patients with Severe Chronic Neutropenia

Diagnosis of Congenital, Cyclic or Idiopathic Neutropenia

Care should be taken to confirm the diagnosis of congenital, cyclic or idiopathic neutropenia, which may be difficult to distinguish from myelodysplasia before initiating Grastofil therapy. The safety and efficacy of Grastofil in the treatment of neutropenia or pancytopenia due to other haematopoietic disorders (for example [e.g.] myelodysplastic syndrome) has not been established.

It is therefore essential that serial complete blood counts with differential and platelet counts and an evaluation of bone marrow morphology and karyotype, be performed prior to initiation of Grastofil therapy.

Myelodysplasia (MDS) and acute myeloid 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 been observed in patients treated with filgrastim for aplastic anemia and severe chronic neutropenia (SCN). Based on available data, the risk of developing MDS and AML has been confined to the subset of patients with congenital neutropenia. Abnormal cytogenetics has been associated with the eventual development of myeloid leukemia. The effect of continued filgrastim administration in patients with abnormal cytogenetics is unknown. If a patient with SCN develops abnormal cytogenetics, the risks and benefits of continuing filgrastim should be carefully considered.

Chronic Administration

The safety and efficacy of the chronic administration of Grastofil have not been studied. The safety and efficacy of chronic daily administration of the reference product (Neupogen) in patients with SCN have been established in Phase I/II clinical trials of 74 patients treated for up to 4.5 years, and in a Phase III trial of 123 patients treated for up to 3.5 years.

Although the relationship to the reference product (Neupogen) is unclear, osteoporosis has been reported in approximately 7% of patients receiving filgrastim therapy for up to 4.5 years in clinical trials in patients with SCN. Decreased bone density and osteoporosis have also been seen in the pediatric patients with SCN in the post-market setting. Patients with SCN, particularly those patients with congenital neutropenia and those with underlying osteoporotic bone disease, should be monitored for the possible occurrence of bone density changes while on long-term filgrastim therapy. Other infrequently observed adverse events included exacerbation of some pre-existing skin disorders (e.g. psoriasis), cutaneous vasculitis (leukocytoclastic), alopecia, haematuria/proteinurea, thrombocytopenia (platelets <0 × 10⁹/L).

Patients with HIV Infection

Risks Associated with Increased Doses of Myelosuppressive Medications 

Treatment with filgrastim alone does not preclude thrombocytopenia and anemia due to myelosuppressive medications. As a result of the potential to receive higher doses or a greater number of these medications with filgrastim therapy, the patient may be at a higher risk of developing thrombocytopenia and anemia. Regular monitoring of blood counts is recommended.

Infections Causing Myelosuppression

Neutropenia may be due to bone marrow infiltrating opportunistic infections such as Mycobacterium avium complex or malignancies such as lymphoma. In patients with known bone marrow infiltrating infection or malignancy, consideration should be given to appropriate therapy for treatment of the underlying condition, in addition to administration of Grastofil for treatment of neutropenia.

Special Populations

Pregnancy and Nursing Women

Filgrastim has been shown to cause adverse effects in pregnant rabbits when given in doses 2 to 10 times the human dose.

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

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

There are cases in the literature where the transplacental passage of filgrastim has been demonstrated. Grastofil should be used during pregnancy only if the potential benefit justifies any potential risk to the fetus.

It is not known whether filgrastim is excreted in human milk, therefore Grastofil is not recommended for use in nursing women.

Pediatrics

Grastofil has not been studies in children under the age of 18, patients with moderate or severe hepatic impairment, or in patients with severe renal impairment. These issues have been addressed through appropriate labelling in the Grastofil Product Monograph.

Safety Conclusion

The safety profile of Grastofil is in general consistent with the known safety profile of the reference product Neupogen. Based on the Grastofil clinical studies, no new significant safety signals were observed in either healthy volunteers or in breast cancer patients. In addition, with the reference product Neupogen being known as a relatively safe drug product with an acceptable safety profile, this further contributes to the overall safety profile of Grastofil. However, given the reduced clinical package submitted which is consistent with all filings of SEB submissions, data for identifying all potential differences between a Subsequent Entry Biologic (SEB) and its reference product regarding long‑term safety is limited. As a result, post‑marketing monitoring of Grastofil for long‑term safety in large patient populations will still be required.

For more information, refer to the Grastofil Product Monograph, approved by Health Canada and available through the Drug Product Database.