Filgrastim

When ATH:
L03AA02

Characteristic.

Stimulator leykopoeza. Produced laboratory strain of bacteria Escherichia coli, in which genetically engineered gene is introduced granulocyte colony Human Factor.

Sterile, colorless liquid for parenteral administration. Molecular weight 18800 Yes.

Pharmacological action.
Leukopoietic.

Application.

Neutropenia (incl. patients, receiving cytotoxic drugs over non-myeloid malignancies); reduction in duration of neutropenia and its clinical consequences in patients, preparing for a bone marrow transplant; persistent neutropenia in patients with advanced HIV infection (absolute neutrophil count 1000 cells / ml or less); mobilization of peripheral blood stem cells (incl. after myelosuppressive therapy); neutropenia (hereditary, recurrent or idiopathic is the number of neutrophils is below or equal to 500 cells /) and severe or recurrent infections (history) in the last 12 Months.

Contraindications.

Hypersensitivity, severe congenital neutropenia when abnormal cytogenetics (Kostmann syndrome), increasing the dose of cytotoxic chemotherapeutic agents above recommended, liver and / or kidney failure, Age to 1 year.

Restrictions apply.

Malignant and premalignant disease myeloid nature, combination with high-dose therapy.

Pregnancy and breast-feeding.

When pregnancy is possible, if the effect of therapy outweighs the potential risk to the fetus (adequate and well-controlled studies have been conducted, Safety in pregnant women has not been established). Use in nursing mothers is not recommended (unknown, whether filgrastim gets into breast milk).

In a study in rabbits shows, filgrastim that causes side effects in pregnant rabbits when taking it at doses, 2-10 times the human dose. When administered to rabbits in doses filgrastim 80 mg / kg / day was observed an increased frequency of miscarriages and embrioletalnosti. Filgrastim, introduced pregnant rabbits at doses 80 ug / kg / day during organogenesis, It led to the urogenital bleeding, reduce food intake, increase in fetal resorption, maldevelopment, weight loss, the number of viable pups. External anomalies were observed in fetuses of females, dosed 80 ug / kg / day.

Studies in pregnant rats at daily / injections in the period of organogenesis at dose levels up 575 mg / kg / day showed no signs of mortality, teratogenicity and behavioral effects in the offspring.

Side effects.

Cancer patients, receiving myelosuppressive chemotherapy

In clinical studies involving over 350 patients, treated with filgrastim after cytotoxic chemotherapy, Most of the side effects was the main complication of a malignant disease or cytotoxic therapy. In Phase II and III studies filgrastim treatment is accompanied by pain in the bones of 24% patients. Usually, these pains were mild or moderate in most cases, they were stopped by conventional analgesics; rare bone pain was severe and required administration of narcotic analgesics. Bone pain was observed more frequently in patients, receiving filgrastim / in high doses (20-100 Mg / kg / day) and less often — in patients, receiving filgrastim n / a in low doses (3-10 Mg / kg / day).

In a randomized, double-blind, placebo-controlled trials in the treatment of filgrastim (4-8 Mg / kg / day) after combination chemotherapy for patients (N=207) with NSCLC were observed adverse reactions (cm. table). Undesirable effects are presented, observed in patients, treated with filgrastim / chemotherapy and placebo / chemotherapy.

Table

Side effects, It is noted in clinical trials

In this study, no serious noted, life-threatening or even fatal reactions, related to filgrastim therapy.

Spontaneous reversible mild to moderate increase in the levels of uric acid, LDH, AP at 27-58% of 98 patients, receiving filgrastim after cytotoxic therapy. In Phase III clinical trials in 7 from 176 patients reported transient decrease in blood pressure (<90/60 mm Hg. Art.) after administration of filgrastim, It does not require additional treatment. Cardiac Effects (myocardial infarction, arrhythmia) It was reported in 11 from 375 cancer patients, filgrastim treated in clinical trials; their causal relationship with filgrastim therapy has not been established.

Cancer patients with bone marrow transplantation

In clinical studies in patients, intensive chemotherapy after bone marrow transplantation, the most common adverse events in the control, and in the study group were stomatitis, nausea and vomiting, mainly mild or moderate expression; connection with the reception of filgrastim is not installed. In a randomized study of 167 patients patients, receiving filgrastim more frequently, than in the control group, the following effects (in parenthesis indicates the percentage of patients in the placebo group): nausea (10/4), vomiting (7/3), hypertension (4/0), rash (12/10), peritonitis (2/0). The causal relationship of these effects to filgrastim therapy has not been established. It reported one case of erythema nodosum and moderate severity, perhaps, related to filgrastim therapy.

Generally, side effects, observed in the non-randomized studies, It was similar to the randomized trials and had mild or moderate severity. In one study (N=45) It was recorded 3 cases of serious side effects in connection with therapy filgrastimom-renal failure (2), Syndrome of increased capillary permeability (1). Communication with the reception of these cases remains unclear filgrastim, tk. They were recorded in patients with proven infection with clinical signs of sepsis, who received potentially nephrotoxic antibacterial and / or antifungal drugs.

In clinical trials, approximately 33% patients were marked bone pain or mild to moderate severity. In most cases, the pain stoped conventional analgesics. Besides, symptoms, occurring with greater frequency when receiving filgrastim compared to placebo, It was generalized musculoskeletal pain. Approximately 30% patients had an enlarged spleen. Thus in patients with palpable spleen infrequently observed abdominal pain or pain in the side, and thrombocytopenia (<50000 cells / mm³ in 12% patients). Less 3% patients (most of them had splenomegaly) They were subjected to splenectomy. Less than 6% patients were thrombocytopenia (<50000 cells / mm³) during filgrastim therapy, Most of them had previous thrombocytopenia. In most cases, thrombocytopenia was held with dose reduction or cessation of therapy. Besides, in 5% patients had platelet counts 50000-100000 / mm³. These patients were observed in receiving filgrastim serious bleeding complications. Nasal bleeding was observed in 15% patients, treated with filgrastim, but has been associated with thrombocytopenia have 2% patients. Anemia was observed in approximately 10% patients, but in most cases it has been associated with frequent diagnostic phlebotomy, chronic disease or concomitant medication. In clinical trials, when receiving filgrastim approximately 3% patients (9/325) razvyvalys myelodysplazyya or leukemia. In 12 from 102 patients with normal cytogenetic assessment at the beginning, They were subsequently detected violations, including monosomiju 7 with repeated assessments after 18-months of therapy 52 filgrastimom. Unknown, whether the development of these phenomena result of continuous or daily administration of filgrastim reflects the natural evolution of SCN. Side effects, perhaps, related to filgrastim therapy and notes in less than 2% patients with SCN, included: injection site reactions, Headache, enlargement of the liver, joint pain, osteoporosis, kozhnыy vasculitis, hematuria and proteinuria, hair loss, each eruption, exacerbation of certain skin diseases previously available (such as psoriasis).

The safety and efficacy of filgrastim administration in the same day, as myelosuppressive cytotoxic chemotherapy drugs, not set. In view of the sensitivity of rapidly dividing myeloid cells to myelosuppressive cytotoxic chemotherapy, assign Filgrastim in the interval for 24 h before and after the introduction of these drugs is not recommended. Preliminary data from a small number of patients, simultaneously receiving filgrastim and 5-fluorouracil, show, that the severity of neutropenia may be exacerbated. Possible interactions with other hematopoietic growth factors and cytokines in clinical trials has not been studied.

Overdose.

In cancer patients, receiving filgrastim on background myelosuppressive therapy, It is advised to avoid the risk of excessive leukocytosis; filgrastim should be discontinued, if the absolute neutrophil count greater than 10,000 / mm³. In clinical trials, filgrastim in patients with cancer, receiving myelosuppressive chemotherapy, less than 5% patients had leukocytosis with a white blood cell counts >100000/mm³. There are no side effects, directly linked with leukocytosis, not disclosed. Within 1-2 days after discontinuation of the drug the number of circulating neutrophils is usually reduced by 50%, with a return to normal in 1-7 days.

P / (rather) or I / (infusion), 1 once a day. Selection of the route of administration depends on the particular clinical situation. The dosage is determined individually depending on indications, severity of the process, the sensitivity of the patient. Treatment begin no earlier than 24 hours after chemotherapy. Zitotoksicski induced neutropenia is usually 0,5 million u/kg/day; mieloablatius therapy with bone marrow transplant — 1 million u/kg/day; mobilization of progenitor cells, gemopoaiza — 1 million u/kg per day for 6 days; and severe chronic neutropenia-initial dose 1,2 million u/kg/day; malignant or periodic neutropenia-initial dose 0,5 million u/kg/day. Treatment continued until the restoration of normal neutrophil (typically up to 14 days). Following induction and consolidation treatment of acute myeloid leukemia the duration of treatment can be increased to 38 d.

Filgrastim therapy should be conducted only under the supervision of a physician or a hematologist-oncologist, with experience in the use of such drugs.

Growth of malignant cells. G-CSF can cause the growth of myeloid cells in vitro. Similar effects may occur in vitro and in respect of some non-myeloid cells. The safety and efficacy of filgrastim in patients with myelodysplastic syndrome or chronic myelogenous leukemia have not been established, therefore in these diseases is not shown in. Particular attention should be paid to the differential diagnosis between blast transformation of chronic myeloid leukemia and acute myeloid leukemia.

Leukocytosis. Given the potential risk, associated with severe leukocytosis, during treatment with filgrastim should regularly monitor the number of white blood cells: if it exceeds 50000 cells / mm³, the drug should be discontinued. When applied filgrastim for the mobilization of peripheral blood stem cells, it overturned, if the number of cells exceeds 100,000 / mm³.

Risk, associated with high-dose chemotherapy. Be particularly careful when treating patients, receiving high-dose chemotherapy, because it was not shown to improve the outcome of cancer, while higher doses of chemotherapeutic agents exhibit more pronounced toxicity, including heart, Pulmonary, neurologic and dermatologic reactions. Monotherapy filgrastim not prevent thrombocytopenia and anemia, due to myelosuppressive chemotherapy. Because of the possibility of using higher doses of chemotherapy (e.g. full doses according to the schemes), the patient may be at greater risk of thrombocytopenia and anemia. It is recommended to regularly monitor the platelet count and hematocrit. Particular caution should be exercised when using single-component or combination chemotherapeutic regimens, It is known for its ability to cause severe thrombocytopenia.

Transformation to leukemia or predleykoz. Particular caution should be exercised in the diagnosis of severe chronic neutropenia, to differentiate them from other hematological disorders, such as aplastic anemia, myelodysplasia and myeloid leukemia. Before treatment should be carried out a detailed analysis of the definition of blood leukocyte and platelet counts, and also to investigate the morphological picture of the bone marrow and karyotype. If the patient syndrome Kostmann appear cytogenetic violations, you need to carefully evaluate the risks and benefits of continued therapy. With the development of myelodysplastic syndrome or leukemia drug should be discontinued. It is not clear, predisposes whether long-term treatment of filgrastim in patients with severe congenital neutropenia (Kostmann syndrome) the development of cytogenetic abnormalities, myelodysplasia and leukemia. Patients with hereditary neutropenia should be regularly (every 12 Months) conduct morphological and cytogenetic studies of bone marrow.

Formula Blood. During treatment, especially during the first few weeks, must carefully monitor the number of platelets. When thrombocytopenia (stable platelet count <100000 cells / mm³), should consider dose reduction or temporary elimination of the drug. There are also other changes in blood counts, requires careful monitoring, incl. anemia and transient increase in the number of myeloid progenitor cells.

Before the appointment to exclude such causes transient neutropenia, as viral infections.

In the treatment of filgrastim should regularly monitor the size of the spleen (palypatsiya life). Reducing the dose of filgrastim in conducting studies to slow or stop the increase in the spleen.

Cooperation