Filgrastim-Nanoleuk - instructions for use, dose, side effects, contraindications

Auxiliary components: sorbitol 50.00 mg and 25.00 mg; polysorbate 80 0.04 mg and 0.02 mg; Acetic acid ice 0.60 mg and 0.30 mg; sodium hydroxide 0.06 mg and 0.03 mg; water for injection up to 1 ml and up to 0.5 ml.

Description:Pcolorless liquid.

Pharmacotherapeutic group:leukopoiesis stimulant

ATX: & nbsp

L.03.A.A.02 Filgrastim

Pharmacodynamics:

Filgrastim is a highly purified, non-glycosylated protein consisting of 175 amino acids produced by the strain Escherichia coli, in the genome of which the gene of granulocyte human colony-stimulating factor (G-CSF) was introduced by genetic engineering. Human G-CSF regulates the formation of functionally active neutrophils and their release into the blood from the bone marrow. Dose-dependent increases the number of neutrophils with normal or increased functional activity. At the end of therapy, the number of circulating neutrophils is reduced by 50% in 1-2 days and returns to the normal amount within 2-7 days.

The use of filgrastim for patients receiving cytotoxic chemotherapy leads to a significant reduction in the frequency, severity and duration of neutropenia and febrile neutropenia.

Pharmacokinetics:

With subcutaneous and intravenous administration, a linear correlation is observed between the administered dose and the concentration of the FILGRASTIM-NANOLECE preparation in the blood serum. After subcutaneous administration of the recommended doses, the concentration in the serum remained above 10 ng / ml for 8-16 hours. The volume of distribution in the blood is approximately 150 ml / kg. The half-life of the drug from serum is approximately 3.5 hours, the clearance is approximately 0.6 ml / min.

Indications:

Neutropenia, febrile neutropenia in patients receiving intensive myelosuppressive chemotherapy for malignant diseases (except chronic myelogenous leukemia and myelodysplastic syndrome), as well as neutropenia and its clinical consequences in patients receiving myeloablative therapy followed by allogeneic or autologous transplantation of hemopoietic cells.

Mobilization of progenitor cells in peripheral blood (KPPK), including after myelosuppressive therapy.

Severe congenital, periodic or idiopathic neutropenia (absolute number of neutrophils ≤ 0.5x10⁹/ l) in children and adults with severe or recurrent infections in the anamnesis.

Persistent neutropenia (absolute number of neutrophils ≤ 1.0x10⁹/ l) in patients with developed stage of HIV infection to reduce the risk of bacterial infections when other methods of treatment are not possible.

Contraindications:

Hypersensitivity to the components of the drug (including colony-stimulating factors, Escherichia coli), severe congenital neutropenia (Costman's syndrome) with cytogenetic disorders; Do not use to increase doses of cytostatic chemotherapeutic drugs above recommended; simultaneous use with cytotoxic chemo- and radiotherapy; terminal stage of chronic renal failure; lactation period; the period of the newborn (during the first 28 days of life).

Carefully:

Pregnancy, malignant and premalignant diseases of a myeloid nature, a combination with high-dosage chemotherapy.

Pregnancy and lactation:

Safety of the preparation FILGRASTIM-NANOLEC for pregnant women is not established. In the literature there are reports in which it is demonstrated that filgrastim penetrated the placental barrier in pregnant women.In pregnancy, the expected therapeutic effect for the mother should be correlated with the possible risk of using the drug for the fetus.

It is not known whether recombinant G-CSF penetrates into the human breast milk. Since many drugs are excreted in human breast milk, breastfeeding should be discontinued when a recombinant G-CSF is administered to a nursing woman.

Dosing and Administration:

It is applied subcutaneously or intravenously.

If the drug is diluted to a concentration of less than 1.5 million units (15 μg) / ml, then the solution should be added with whey human albumin, so that the final albumin concentration is 2 mg / ml (for example, with a final solution volume of 20 ml, the total dose of the drug is less than 30 million units (300 μg) should be administered with the addition of 0.2 ml of 20% human albumin solution.

Do not dilute the drug to a final concentration of less than 0.2 million ED (2 μg) in 1 ml.

The ready solution should be stored at a temperature of 2-8 ° C for not more than a day.

The first dose of the drug should be administered no earlier than 24 hours after cytotoxic chemotherapy, and when bone marrow transplantation - no later than 24 hours after the infusion of the bone marrow.

Constant chemotherapy with cytotoxic agents

The recommended dose of FILGRASTIM-NANOLEC is 0.5 million units (5 μg) / kg once a day.

The first dose of FILGRASTIM-NANOLEC should be administered no earlier than 24 hours after cytotoxic chemotherapy. FILGRASTIM-NANOLEC can be administered by daily subcutaneous injections or daily 30-minute intravenous infusions after dilution in a 5% glucose solution. In most cases, subcutaneous administration is preferred.

Daily administration of the preparation FILGRASTIM-NANOLEC should continue until the number of neutrophils passes through the expected minimum, and does not reach normal values. After constant chemotherapy in the treatment of solid tumors, lymphomas and lymphoblastic leukemia, it is estimated that the duration of treatment required to meet these criteria is up to 14 days. After induction and consolidation of treatment for acute myeloid leukemia, the duration of treatment can be much longer (up to 38 days), depending on the type, dose and scheme of the cytotoxic chemotherapy used.

Not recommended prematurely discontinue treatment with FILGRASTIM-NANOLEC until the number of neutrophils exceeds the expected minimum. Treatment is stopped if the absolute number of neutrophils after nadir reached 1 thousand / μl.

For patients who received myeloablative therapy followed by bone marrow transplantation

The recommended initial dose is 1.0 million units (10 μg) / kg / day and is administered by a 30-minute or 24-hour intravenous infusion, or 1.0 million units (10 μg) / kg / day, administered by continuous subcutaneous 24-hour infusion. FILGRASTIM-NANOLEC should be diluted in 20 ml of 5% glucose solution.

The duration of therapy is no more than 28 days.

After the maximum reduction in the number of neutrophils (nadir), the daily dose is adjusted depending on the dynamics of the number of neutrophils. If the number of neutrophils exceeds 1 thousand / μL for 3 consecutive days, the dose is reduced to 0.5 million units (5 μg) / kg / day; then, if the absolute number of neutrophils exceeds 1 thousand / μL for 3 consecutive days, the drug is canceled. If during the treatment period the absolute number of neutrophils decreases less than 1 thousand / μl, the dose is again increased in accordance with the above scheme.

For the mobilization of progenitor cells in peripheral blood (CPAP) in patients receiving myelosuppressive or myeloablative therapy with followed by autologous KPAC transplantation

The recommended dose for mobilizing KPPP as an independent therapy is 1.0 million units (10 μg) / kg / day by continuous 24-hour subcutaneous infusion or subcutaneous injection once a day for 5-7 consecutive days.

The recommended dose for mobilizing KPPK after myelosuppressive chemotherapy is 0.5 million units (5 μg) / kg / day and is injected daily by subcutaneous injection starting from the first day after completion of chemotherapy and until the number of neutrophils passes through the expected minimum and will not recover to normal values.

Leukapheresis should be performed during the period when the absolute number of neutrophils rises from <0.5x10⁹/ l to> 5,0x10⁹/ l.

To mobilize progenitor cells in peripheral blood (CPAP) in healthy donors before autologous KPPC transplant

To mobilize KPAT in healthy donors, FILGRASTIM-NANOLEC should be administered subcutaneously at a dose of 1.0 million ED (10 μg) / kg / day for 4-5 consecutive days.Leukapheresis should be started on the 5th day and, if necessary, continue until the 6th day to collect 4x10⁶ Cd34+- cells / kg body weight of the recipient.

Patients with severe chronic neutropenia

Congenital neutropenia: the recommended initial dose is 1.2 million units (12 μg) / kg / day, subcutaneously as a single dose or divided into several administrations.

Idiopathic or cyclic neutropenia: the recommended initial dose is 0.5 million units (5 μg) / kg / day subcutaneously as a single dose or divided into several administrations.

Correction of dose: FILGRASTIM-NANOLEC should be administered daily by subcutaneous injection until the number of neutrophils is consistently greater than 1.5 x 10⁹/ l. After achieving the effect, you need to determine the minimum effective dose to maintain this level. To maintain an adequate number of neutrophils requires a long daily administration of the drug. After 1-2 weeks of treatment, the initial dose can be doubled or halved, depending on the patient's response to therapy.

The daily dose should not exceed 24 mcg / kg / day.

Pediatric use in severe chronic neutropenia (TCN) and oncological diseases

The data obtained from clinical studies in the pediatric group of patients show that the efficacy and safety of FILGRASTIM-NANOLEC are similar for adults and children receiving cytotoxic chemotherapy. Recommendations for dosing for patients in the pediatric group are the same as for adults receiving myelosuppressive cytotoxic chemotherapy.

For patients with HIV infection

The recommended initial dose is 0.1 million ED (1 μg) / kg / day administered daily by subcutaneous injection with a titration of up to 0.4 million ED (4 μg) / kg / day until normal and a stable number of neutrophils (absolute number of neutrophils>2,0x10⁹/ l). In clinical studies> 90% of patients responded positively to these doses, achieving neutropenia reversibility on average after 2 days.

A small number of patients (<10%) to achieve reversibility of neutropenia, doses up to 1.0 million ED (10 μg) / kg / day were required.

After achieving neutripenia reversibility, it is necessary to establish a minimum effective dose to maintain a normal number of neutrophils. Recommended correct the initial dose alternating every other day with a dose of 30 million units / day (300 μg / day), injected by subcutaneous injection. Subsequently, to maintain the number of neutrophils> 2.0x10⁹/ l, an individual dose adjustment may be required, depending on the absolute number of neutrophils in the patient. In clinical studies, a dose of 30 million units / day (300 μg / day), administered 1-7 days per week, was required to maintain an absolute number of neutrophils> 2.0 × 10⁹/ l, with an average frequency of dosing 3 days a week. To maintain the absolute number of neutrophils> 2.0x10⁹/ l may require long-term use of the drug.

Special instructions for dosing

Elderly age: There are no specific recommendations.

Children: in patients with severe chronic neutropenia and oncological diseases, the safety profile did not differ from that in adults. The dosage regimen in children is similar to that of adult patients. In patients with severe renal or hepatic insufficiency, dose adjustment is not required.

Side effects:

Are common: headache, fatigue, weakness, reactions at the injection site (less than 2% of patients with severe chronic neutropenia).

From the side of the musculoskeletal system: often weak or moderate (10%), sometimes severe (3%) osalgia and myalgia (in most cases, stop with non-steroidal anti-inflammatory drugs (NSAIDs), arthralgia, osteoporosis, acute gouty arthritis, exacerbation of rheumatoid arthritis.

From the digestive system: diarrhea, constipation, hepatomegaly.

From the side of the cardiovascular system: very rarely - a transient decrease in blood pressure (BP) (not requiring medication correction), veno-occlusive disease (no connection with the drug intake), skin vasculitis (with prolonged therapy in 2% of patients with severe chronic neutropenia), arrhythmia not installed).

From the respiratory system: interstitial pneumonia (there is no connection with the drug intake) potentially with an unfavorable prognosis (after chemotherapy, especially the regimens including bleomycin), pulmonary edema and infiltrates in the lungs, respiratory distress syndrome in adults, respiratory failure, cough, sore throat.

From the skin: alopecia (hair loss), skin rash, rarely - Sweet syndrome (acute febrile neutrophilic dermatosis, communication with the drug is not established).

On the part of the organs of hematopoiesis and the system of hemostasis: splenomegaly, pain in the upper left quadrant of the abdomen; rarely - thrombosis of blood vessels; very rarely - rupture of the spleen, thrombocytopenia, anemia, nasal bleeding (with long-term administration), leukocytosis, myelodysplastic syndrome and leukemia (in 3% of patients with severe congenital neutropenia - Costman's syndrome) - there is no connection with the drug.

From the genitourinary system: rarely - violation of urination.

Allergic reactions: rarely - skin rash.

Laboratory indicators: reversible dose-dependent (usually not expressed or moderate) increased activity of lactate dehydrogenase (LDH), alkaline phosphatase (FA), gamma-GT (gamma-glutamyltransferase), hyperuricemia, transient hypoglycemia after eating; very rarely - proteinuria, hematuria.

Overdose:

Cases of overdose are not registered. On the background Myelosupressive therapy prolonged use of the drug led to a decrease in the number of circulating neutrophils by 50% 1-2 days after the withdrawal of the drug, which returned to normal after 1-7 days.

Interaction:

5-fluorouracil increases the severity of neutropenia.

In view of the sensitivity of rapidly developing myeloid cells to myelosuppressive cytotoxic chemotherapy, it is not recommended to use FILGRASTIM-NANOLEC in a period beginning 24 hours before chemotherapy and ending 24 hours after chemotherapy.

Pharmaceutically incompatible with 0.9% solution of sodium chloride.

Special instructions:

Treatment with the drug should be carried out only under the supervision of an oncologist or hematologist with experience in the use of such drugs, provided that the necessary diagnostic capabilities are available.

Procedures for mobilization and apheresis of cells should be carried out in specialized centers with work experience and the possibility of adequate control of progenitor cells.

In the process of treatment, control of the number of leukocytes and the cellular composition of the bone marrow should be carried out.

The drug solution is prepared no earlier than 24 hours prior to administration and stored at a temperature of 2-8 ° C.

The efficacy and safety of the drug for mobilizing KPAC in healthy donors under the age of 16 and older than 60 years for allogeneic transplantation have not been studied.

Granulocyte colony stimulating factor of a person can stimulate the growth of myeloid cells in vitro and for non-myeloid cells.

Safety and efficacy in the use of myelodysplastic syndrome and chronic myelogenous leukemia have not been established.

Particular attention should be paid to differential Diagnosis between blasttransformation of chronic myelogenous leukemia and acute myeloid leukemia.

Patients receiving cytotoxic chemotherapy: less than 5% of patients receiving treatment at a dose of more than 0.3 million units. (3 μg) / kg / day, the number of leukocytes increased to 100 thousand / μL or more. There were no side effects associated with this. However, considering the possible risk associated with severe leukocytosis, during treatment it is necessary to regularly determine the number of leukocytes. If the expected minimum is more than 50 thousand / mkl, the drug should be immediately canceled. If the drug is used to mobilize PBPCs, it is canceled if the number of white blood cells exceeds 100 thousand. / Ml.

Particular caution should be exercised in patients receiving high dose chemotherapy because of improving the outcome of cancer has not been shown, while high-dose chemotherapy have a more pronounced toxicity, including cardiovascular, pulmonary, neurological and dermatological reactions.

Monotherapy with the drug does not prevent the development of thrombocytopenia and anemia caused by myelosuppressive chemotherapy. Because of the possibility of using higher doses of chemotherapy (eg, full doses according to the regimens), the patient may be at greater risk of thrombocytopenia and anemia. It is recommended to regularly determine the number of platelets and hematocrit. Particular caution should be exercised when using single-component or combined chemotherapeutic regimens capable of causing severe thrombocytopenia.

The use of KPPK, mobilized with the drug, reduced the severity and duration of thrombocytopenia after myelosuppressive or myeloablative chemotherapy.

Particular care should be taken when diagnosing severe chronic neutropenia to differentiate them from other hematological diseases, such as aplastic anemia, myelodysplasia and myeloid leukemia.

Prior to treatment should be carried out with the full blood count and determination of leukocyte platelet counts, as well as explore morphologic picture of bone marrow and karyotype.

A small number (3%) of patients with severe congenital neutropenia (Costman's syndrome) who received the drug, observed myelodysplastic syndrome (MDS) and leukemia. MDS and leukemia are natural complications of this disease. Their relationship with the treatment of the drug is unclear. Approximately 12% of patients with initially normal cytogenetics had anomalies during a second examination, including monosomy 7. If a patient with Costman's syndrome develops cytogenetic disorders, the benefits and risks of continuing therapy should be carefully evaluated. With the development of MDS or leukemia drug should be canceled. It is not yet clear whether long-term treatment with a drug of patients with severe congenital neutropenia (Costman's syndrome) predisposes to the development of cytogenetic abnormalities, MDS and leukemia. Patients with Costman's syndrome are recommended to perform morphological and cytogenetic studies of the bone marrow at regular intervals (every 12 months).

During the treatment period, the number of platelets must be carefully monitored, especially during the first few weeks of treatment with the drug.In case of development of thrombocytopenia (the number of platelets stably below 100 thousand / μl) should be considered the question of the temporary withdrawal of the drug or a decrease in the dose. There are also other changes in the blood formula that require careful monitoring, including anemia and a transient increase in the number of myeloid progenitor cells.

It is necessary to exclude such causes of transient neutropenia as viral infections. The enlargement of the spleen is a direct consequence of the treatment with the drug. During clinical studies, in 31% of patients with severe chronic neutropenia, palpation showed splenomegaly. Radiography showed an increase in the spleen soon after treatment and tended to stabilize. It was found that a decrease in dose slowed or stopped splenomegaly; 3% of patients required splenectomy. The size of the spleen should be monitored regularly. To detect splenomegaly, it is enough to produce a palpation of the abdomen.

A small number of patients had hematuria and proteinuria. Urine test should be monitored regularly.

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

Mobilization: prospective randomized trials comparing two recommended mobilization methods (only filgrastim or in combination with myelosuppressive chemotherapy) were not performed on the same contingent of patients. The degree of discrepancy between the results of individual patients and the results of a laboratory determination of the number Cd34⁺-cells shows that direct comparison of various studies is difficult. Therefore, it is difficult to recommend an optimal method. The choice of method of mobilization should be made depending on the overall goals of the treatment of the patient.

Prior treatment with cytostatic drugs: in patients who have had an active myelosuppressive therapy, there may not be sufficient activation of the KPTC up to the recommended minimum number (more than 2 million) Cd34⁺/ kg) or acceleration of the normalization of the number of platelets.

Some cytostatics have a particular toxicity to the precursor cells of hemopoiesis and can adversely affect their mobilization.Such medicines as melphalan, carmustine and carboplatin, if they were prescribed for a long time before attempts to mobilize progenitor cells, may reduce its effectiveness. However, their application simultaneously with the drug proved to be effective when activation of progenitor cells.

If a transplantation of peripheral progenitor cells is planned, it is recommended that the stem cells be mobilized at an early stage of treatment. Particular attention should be paid to the number of progenitor cells activated in such patients before high-dose chemotherapy. If the results of mobilization in accordance with the above criteria are not sufficient, alternative treatments that do not require the use of progenitor cells should be considered.

Estimating the number of progenitor cells mobilized in patients with the drug, special attention should be paid to the method of quantitative determination. Results of flow cytometric analysis of the number Cd34⁺-cells differ depending on the specific methodology; it is necessary to be cautious about the recommendations on their number, based on studies conducted in other laboratories.

Statistical analysis of the relationship between the number of entered Cd34⁺-cells and the rate of normalization of the number of platelets after high-dose chemotherapy indicates a complex but stable dependence.

Currently, the minimum value of growth Cd34⁺-cells is not yet sufficiently defined.

Form release / dosage:

Solution for intravenous and subcutaneous administration, 30 million units / 1 ml, 48 million units / 0.5 ml.

Packaging:

For 1.0 ml (30 million units / 1 ml) of the drug in a glass syringe (type I, USP). One pre-filled syringe (with a soldered needle, elastomeric cap and plastic hard polypropylene hood, and also a plastic polystyrene or polypropylene rod with elastomeric piston) in a plastic or cardboard holder in a cardboard box with the first opening in the form of a sticker together with the instruction for use.

0.5 ml (48 million units / 0.5 ml) of the drug in a glass syringe (type I, USP). One pre-filled syringe (with a soldered needle, elastomeric cap and plastic hard polypropylene hood, as well as a plastic polystyrene or polypropylene rod with elastomeric piston) in a plastic or cardboard holder in a cardboard box with a first opening control in the form of a sticker together withinstructions for use.

Storage conditions:

At a temperature of 2 to 8 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-002698/10

Date of registration:31.03.2010 / 01.08.2014

Expiration Date:Unlimited

The owner of the registration certificate:NANOLEC, LTD. NANOLEC, LTD. Russia

Manufacturer: & nbsp

INTAS PHARMACEUTICALS, Ltd. India

Representation: & nbspNANOLEC, LTD.NANOLEC, LTD.

Information update date: & nbsp07.01.2017

Illustrated instructions

Instructions

Filgrastim-Nanolek (Filgrastim-Nanolek)