Filgrastim

Characteristic

Filgrastim is a highly purified non-glycosylated polypeptide containing 175 amino acid residues.

M-T-P-L-G-P-A-S-S-L-P-Q-S-F-L-L-K-C-L-E-Q-V-R-K-I-Q-G-D-G-A-A-L-

Q-E-K-L-C-A-T-Y-K-L-C-H-P-E-E-L-V-L-L-G-H-S-L-G-I-P-W-A-P-L-S-S-

C-P-S-Q-A-L-Q-L-A-G-C-L-S-Q-L-H-S-G-L-F-L-Y-Q-G-L-L-Q-A-L-E-G-I-

S-P-E-L-G-P-T-L-D-T-L-Q-L-D-V-A-D-F-A-T-T-I-W-Q-Q-M-E-E-L-G-M-A-

P-A-L-Q-P-T-Q-G-A-M-P-A-F-A-S-A-F-Q-R-R-A-G-G-V-L-V-A-S-H-L-Q-S-

F-L-E-V-S-Y-R-V-L-R-H-L-A-Q-P

C₈₄₅H₁₃₃₆O₂₄₂N₂₂₃S₉M.m .: 18798

It is produced by a genetically modified culture of Escherichia coli BL21 (DE3) / pES3-7 containing the gene for human granulocyte colony stimulating factor (G-CSF).

Human G-CSF regulates the formation of functionally active neutrophilic granulocytes and their entry into the blood from the bone marrow.

Filstim containing recombinant G-CSF significantly increases the number of neutrophilic granulocytes in the peripheral blood within the first 24 hours after administration and at the same time causes a slight increase in the number of monocytes.

An increase in the number of neutrophilic granulocytes, their functional characteristics depend on the dose.

The use of filgrastim preparations significantly reduces the frequency and duration of neutropenia in patients after chemotherapy with cytostatics, myeloablative therapy, followed by bone marrow transplantation.

Patients who received the drug are less likely to need hospitalization, spend less time in the hospital, take lower doses of antibiotics compared to patients who received only cytotoxic therapy.

The use of Filstim (both primary and after chemotherapy) activates peripheral blood progenitor cells (CPPK).

In children and adults with severe chronic neutropenia (severe congenital, periodic and malignant neutropenia), the drug stably increases the number of peripheral blood neutrophilic granulocytes and reduces the incidence of infectious complications.

After treatment with the drug, the number of neutrophilic granulocytes in the peripheral blood decreases by 50% within 1–2 days and returns to normal levels within 1–7 days.

Pharmacological properties

Pharmacokinetics after sc administration of the drug in recommended doses, its concentration in the blood serum exceeds 10 ng / ml for 8-16 hours; the volume of distribution in the blood is about 150 ml / kg. the average value of t½ filgrastim from serum is about 3.5 hours, and the clearance rate is about 0.6 ml / min per 1 kg. continuous infusion for 28 days in patients recovering from an autologous bone marrow transplant was not accompanied by signs of cumulation and an increase in t½ of the drug.

Indications

To shorten the duration and reduce the incidence of neutropenia, including accompanied by a febrile reaction in patients receiving chemotherapy with cytotoxic drugs, with non-myeloid malignant diseases.

To reduce the duration of neutropenia and its clinical consequences in patients receiving myeloablative therapy with subsequent bone marrow transplantation.

To mobilize autologous CPPK, including after myelosuppressive therapy, to accelerate the restoration of hematopoiesis by introducing these cells after myelosuppression or myeloablation.

With prolonged therapy aimed at increasing the number of neutrophilic granulocytes, to reduce the frequency and duration of infectious complications in children and adults with severe congenital, periodic or malignant neutropenia (the absolute number of neutrophilic granulocytes is 500 in 1 mm³) and with severe or recurring infections in the anamnesis.

Application

When conducting cytotoxic chemotherapy according to standard schemes, the drug is prescribed at 0.5 million units (5 μg) per 1 kg of body weight 1 time per day s / c or by iv injection.

In myelo-ablative therapy followed by bone marrow transplantation, the initial dose of filgrastim - 1 million units (10 μg) per 1 kg of body weight per day - is administered iv drip for 30 min or by continuous iv infusion for 24 hours, or PC.

Before iv administration, the drug is diluted in 20 ml of 5% dextrose solution; the first dose is administered no earlier than 24 hours after cytotoxic therapy or bone marrow transplantation.

Filstim is administered daily until the number of neutrophilic granulocytes reaches the expected minimum, and then normal values. The duration of treatment can be up to 14 days, depending on the type of dose and the schedule of cytotoxic chemotherapy.

Against the background of cytotoxic chemotherapy, the incoming increase in the number of neutrophilic granulocytes is usually observed 1-2 days after the start of treatment with Filstim. However, to obtain a stable therapeutic effect, it is necessary to continue therapy until the number of neutrophilic granulocytes passes the expected minimum and reaches normal values. It is not recommended to cancel the drug prematurely until the required minimum value of the number of neutrophilic granulocytes is reached.

After the moment of the maximum decrease in the number of neutrophilic granulocytes passes, the daily dose should be adjusted taking into account the dynamics of their number: if the number of neutrophilic granulocytes exceeds 1000 in 1 mm³ for 3 consecutive days, the dose is reduced to 0.5 million units (5 mcg) / kg per day; then, if the absolute number of neutrophilic granulocytes exceeds 1000 in 1 mm³ also within 3 days, the drug is canceled. If during treatment, the absolute number of neutrophilic granulocytes decreases 1000 in 1 mm³, the dose of the drug must be increased again in accordance with the given scheme.

In severe congenital neutropenia, the drug is administered at an initial dose of 1.2 million units (12 mcg) / kg per day sc once or distribute the daily dose for several administrations.

In severe chronic or periodic neutropenia - 0.5 million units (5 μg) / kg per day s / c once or divided into several administrations.

In patients with severe chronic neutropenia, the drug should be administered daily s / c until the number of neutrophilic granulocytes stably exceeds 1500 in 1 mm³. Once the therapeutic effect is achieved, the effective minimum maintenance dose is determined. To maintain the required number of neutrophilic granulocytes, a long daily administration of the drug is required. After 1-2 weeks of treatment, the initial dose can be doubled or halved, depending on the patients response to therapy. In the future, every 1-2 weeks, you can carry out an individual dose adjustment to maintain the average number of neutrophilic granulocytes in the range of 1500-10 000 in 1 mm³. For patients with severe infections, a regimen with a faster dose increase can be used.

After preparation, the diluted drug solutions should be stored in the refrigerator at a temperature of 2-8 ° C for no more than 24 hours.

Contraindications

Hypersensitivity to the drug. severe congenital neutropenia (Costman syndrome) with cytogenetic disorders.

Side effects

In patients receiving cytotoxic chemotherapy, treatment with filgrastim is often accompanied by pain in the bones and muscles, usually mild or moderate, sometimes intense. in most cases, the pain is stopped by taking analgesics. less often, side effects are manifested by urination disorders (mainly mild or moderate dysuria). There are separate reports of a transient decline in hell that did not require treatment.

Often, a reversible, dose-dependent, usually mild or moderate increase in the concentration of LDH, alkaline phosphatase, uric acid and γ-glutamyl transferase in the blood serum can be observed.

Sometimes, patients receiving high-dose chemotherapy followed by autologous bone marrow transplantation have vascular disorders (e.g. veno-occlusive disease and water-electrolyte imbalance). The causal relationship of their occurrence with the use of the drug has not been established. Rare cases of the development of allergic reactions are described, and about half of them were associated with the introduction of the first dose.These cases were more often observed after iv administration of the drug. Sometimes the resumption of treatment was accompanied by a relapse of allergy symptoms.

In patients with severe chronic neutropenia, adverse reactions are described that arise as a result of filgrastim, and in some of them, the frequency of these reactions decreased over time.

The most common adverse reactions are bone pain and generalized musculoskeletal pain; other side effects include an increase in the size of the spleen, which in a small number of patients can progress, as well as thrombocytopenia; Cases of headache and diarrhea are described shortly after the start of treatment with filgrastim. There are also reports of anemia and nosebleeds that develop only with prolonged use of the drug.

A transient and clinically asymptomatic increase in the serum concentration of uric acid, LDH and alkaline phosphatase, as well as a moderate and reversible decrease in blood glucose after eating, were observed.

In patients with severe chronic neutropenia, side effects, possibly due to the use of filgrastim, were usually observed in less than 2% of patients and were manifested by reactions at the injection site, an increase in liver size, joint pain, hair loss, osteoporosis and skin rash.

With prolonged therapy, 2% of patients with severe chronic neutropenia experienced vasculitis of the skin, in very rare cases, proteinuria and hematuria.

special instructions

G-CSF promotes the growth of myeloid cells in vitro. a similar in vitro effect can be observed in some non-myeloid cells. the safety and effectiveness of filgrastim in patients with myelodysplasia, acute and chronic myeloid leukemia have not been established. due to the possible potentiation of tumor growth, filgrastim should be used with caution in case of malignant diseases of the myeloid nature. for any myeloproliferative disease, filgrastim should be used with caution, given the possible risk of developing leukemia. during treatment with filgrastim, it is necessary to regularly monitor the number of leukocytes; if it exceeds 5000 in 1 mm3, the drug should be discontinued immediately. if the drug is used to mobilize PPC, it is canceled when the white blood cell count exceeds 10,000 in 1 mm3.

Particular care should be taken in the treatment of patients receiving high-dose chemotherapy. Monotherapy with filgrastim does not prevent thrombocytopenia and anemia due to myelosuppressive chemotherapy, however, it allows the use of chemotherapy in higher doses (in accordance with the schemes), as a result of which the patient is at high risk of developing thrombocytopenia and anemia. It is recommended to regularly determine the platelet count and hematocrit. Particular caution should be exercised when using single-component or combined chemotherapeutic regimens that can cause thrombocytopenia.

The use of KPPK mobilized with filgrastim preparations reduces the severity and duration of thrombocytopenia after myelosuppressive or myeloablative chemotherapy.

Particular attention should be paid to the diagnosis of severe forms of chronic neutropenia. It is necessary to differentiate them from hematological diseases such as hypoplastic anemia, myelodysplasia and myeloid leukemia. Before treatment, a detailed blood test is indicated with a leukocyte count and platelet count, as well as a study of the morphological composition of the bone marrow and karyotype.

In patients with severe congenital neutropenia (Costman syndrome) who received filgrastim, in some cases the development of myelodysplastic syndrome and leukemia was observed, but their relationship with treatment with filgrastim has not been established.If cytogenetic disorders are detected in patients with Costmans syndrome, the risk and benefit of continuing with filgrastim therapy should be carefully compared; if myelodysplastic syndrome or leukemia is detected, the drug should be discontinued. At present, it has not been established whether long-term treatment with filgrastim for patients with Costmans syndrome predisposes to the development of leukemia, therefore, patients with this pathology are recommended to regularly conduct a morphological and cytogenetic study of bone marrow (approximately every 12 months).

It is necessary to carefully monitor the platelet count in the peripheral blood, especially during the first few weeks of treatment with filgrastim. If the patient has thrombocytopenia (platelet count is stable below 100,000 in 1 mm³), consideration should be given to temporarily discontinuing the drug or reducing the dose.

Other changes in blood composition are also observed that require constant monitoring, including anemia and a transient increase in the number of immature myeloid cells.

The cause of transient neutropenia, such as viral infections, should be ruled out.

An increase in the size of the spleen is a direct consequence of treatment with filgrastim, so it is necessary to regularly palpate the abdomen to determine the size of the spleen. With a decrease in the dose of the drug, the increase in the size of the spleen slowed down and did not progress. In a small number of patients, hematuria and proteinuria were detected. To monitor them, regular urinalysis should be performed regularly.

Safety and efficacy of the drug in newborns and patients with autoimmune neutropenia have not been established.

In patients who have undergone active myelosuppressive therapy in the past, there may not be sufficient activation of CPPP to the recommended minimum level (2 · 10⁶ CD34-positive cells / kg) or accelerate platelet normalization.

Some cytostatics are particularly toxic to KPPK and can negatively affect their mobilization. Drugs such as melphalan, carmustine (BCNU), and carboplatin, if given for a long time before attempting to mobilize CPPP, can reduce its effectiveness. However, the use of melphalan, carboplatin or carmustine in combination with filgrastim was effective in the activation of CPPK.

If a CPPT transplant is planned, stem cell mobilization at the beginning of treatment is recommended. Particular attention should be paid to the number of progenitor cells activated in such patients prior to the use of high-dose chemotherapy. If the results of mobilization in accordance with the above criteria are insufficient, alternative treatment methods that do not require the use of progenitor cells should be considered. When assessing the number of progenitor cells mobilized in patients with filgrastim, particular attention should be paid to the quantification method. The results of a flow study of the number of CD34-positive cells are distinguished depending on the method used, and caution should be exercised in recommendations based on studies conducted in different laboratories.

Patients with osteoporosis and concomitant bone pathology, receiving continuous treatment with filgrastim for 6 months or more, are shown to monitor bone density.

Filgrastim increases the number of neutrophilic granulocytes by acting primarily on their progenitor cells. Therefore, in patients with a reduced content of progenitor cells (for example, undergoing intensive radiation or chemotherapy), the degree of increase in the number of neutrophilic granulocytes may be lower.

Incompatibility. Not studied.

Use during pregnancy and lactation.The safety of Filstim during pregnancy has not been established, it is not known whether Filstim passes into breast milk, so it is not recommended to use it during lactation.

Influence on the ability to drive vehicles. Not investigated.

Interactions

The safety and efficacy of filstime administration on the same day as myelosuppressive cytotoxic chemotherapy drugs have not been established. due to the sensitivity of rapidly dividing myeloid cells to myelosuppressive cytotoxic chemotherapy, it is not recommended to prescribe filstim in the interval 24 hours before and after administration of these drugs.

Overdose

Symptoms of filstime overdose are unknown.

Storage conditions

In a dark place at a temperature of 2–8 ˚ s.