Tevagrastim, 60 ml/ml 0.5 ml

Interaction

The efficacy and safety of filgrastim administration on the same day as cytotoxic chemotherapy have not been established. Because of the high sensitivity of actively proliferating myeloid cells to anticancer cytotoxic drugs, administration of filgrastim 24 hours before or after administration of these drugs is not recommended.

Fluorouracil increases the severity of neutropenia when administered simultaneously with filgrastim. Possible interaction with other hematopoietic growth factors and cytokines is unknown.

Given that lithium stimulates neutrophil release, it is possible that the effects of filgrastim may be enhanced when administered in combination, but such studies have not been conducted.

Philgrastim is not pharmaceutically compatible with 0.9% sodium chloride solution. When using filgrastim for mobilization of hematopoietic stem cells after chemotherapy it should be considered that the effectiveness of mobilization may be reduced if cytostatics such as melphalan, carmustine and carboplatin are prescribed for a long time.

Special Instructions

The treatment with Tevagrastim should only be performed under the supervision of an oncologist or hematologist experienced in the use of G-CSF, with the necessary diagnostic capabilities. Cell mobilization and apheresis procedures must be performed in an oncology or hematology center experienced in this field and with adequate monitoring of hematopoietic progenitor cells.

Glomerulonephritis

There have been reports of glomerulonephritis in patients receiving filgrastim, lenograstim, or pegfilgrastim. Typically, cases of glomerulonephritis resolve after dose reduction or withdrawal of filgrastim, lenograstim, or pegfilgrastim. Monitoring of urinalysis values is recommended.

There have been reports of aortitis following G-CSF administration. Symptoms may include fever, abdominal pain, malaise, back pain, and be accompanied by elevated levels of inflammatory markers (e.g., C-reactive protein and white blood cell count). In most cases aortitis was diagnosed by CT scan and resolved after withdrawal of G-CSF.

Precautionary measures for patients with acute myeloid leukemia

.Growth of malignant cells

Human G-CSF can stimulate growth of myeloid cells in vitro. Similar effects may be observed in vitro against some nonmyeloid cells.

The efficacy and safety of filgrastim have not been established in myelodysplastic syndrome (MDS) and chronic myeloleukemia. In patients with the above diseases as well as with pre-tumor lesions of myeloid hematopoiesis, filgrastim is not indicated. Particular attention should be paid to the differential diagnosis between blastic crisis of chronic myeloleukemia and acute myeloleukemia.

Cautions must be taken with Tevagrastim in patients with secondary myelocytic leukemia (SML), since there are limited data on safety and effectiveness.

The safety and efficacy of Tevagrastim, used for the first time in patients with ALS under age 55 without cytogenetic abnormalities [t(8; 21), t(15; 17), and inv(16)], have not been established.

Other Precautions

Patients with osteoporosis due to bone disease should have their bone density monitored regularly during long-term (>6 months) use of Tevagrastim.

There have been rare reports of adverse respiratory reactions with G-CSF, particularly interstitial pneumonia. Patients who have recently had infiltrative lung disease or pneumonia may have a high risk. The appearance of symptoms such as cough, elevated body temperature and dyspnea against the background of lung infiltrates detected on radiological examination and signs of worsening lung function may be the first signs of RDSV. In case of RDSV development Tevagrastim should be discontinued and an appropriate therapy should be provided.

The development of capillary permeability syndrome during G-CSF use has been reported, which is accompanied by decreased BP, hypoalbuminemia, edema and hemoconcentration. Patients who develop capillary permeability syndrome should be monitored and symptomatic treatment and resuscitation measures should be given if necessary.

Cautions for patients with cancer

Leukocytosis

In a small number of patients (less than 5%) who received filgrastim at doses greater than 3 micrograms (0.3 million IU)/kg per day observed. IU)/kg/day, leukocytosis (leukocyte count of 100 x 10⁹/l or more) was observed. No adverse events directly related to filgrastim-induced leukocytosis have been described. However, given the possible risks associated with leukocytosis, the leukocyte count should be determined regularly during treatment with filgrastim. If it exceeds 50 x 10⁹/L after passing the expected minimum, filgrastim should be stopped immediately. If filgrastim is used to mobilize hematopoietic stem cells, the drug should be discontinued when the leukocyte count exceeds 70 x 10⁹/l.

Risk associated with high-dose chemotherapy

.Particular caution should be exercised when treating patients receiving high-dose chemotherapy because higher doses of chemotherapy have greater toxicity, including skin reactions and cardiovascular, nervous, and respiratory side effects (see

Monotherapy with filgrastim does not prevent thrombocytopenia and anemia associated with myelosuppressive chemotherapy. Because of the possibility of higher doses of chemotherapy (e.g., full doses according to regimens), the patient may be at greater risk for thrombocytopenia and anemia. It is recommended that blood tests, platelet counts and hematocrit be performed regularly twice a week during the use of filgrastim after chemotherapy. Particular caution should be exercised when using single-component or combined chemotherapeutic regimens that may cause severe thrombocytopenia.

The use of filgrastim to mobilize PSCC has been shown to reduce the severity and duration of thrombocytopenia associated with myelosuppressive or myeloblastic chemotherapy.

Other Precautions

The effect of filgrastim in patients with significantly reduced myeloid progenitor cell counts is not known. Filgrastim increases neutrophil counts by acting primarily on neutrophil precursor cells. Therefore, patients with reduced progenitor cells (e.g., those who have undergone intensive radiation therapy or chemotherapy) may have a lower degree of increase in neutrophil counts.

There have been reports of graft vs. host reactions and deaths in patients treated with H-CSF following allogeneic bone marrow transplantation.

Bone tissue radiographs have revealed increased hematopoietic bone marrow activity in response to human H-CSF therapy. These data should be considered in the analysis of bone radiographs.

Cautions for patients undergoing PSCC mobilization

Bone marrow transplantation is followed by blood tests and platelet counts 3 times per week.

Mobilization

The two recommended methods of mobilization (filgrastim alone or in combination with myelosuppressive chemotherapy) were not compared on the same patient population. The degree of difference in the results of laboratory determination of CD34+ cell counts means that a direct comparison of the different studies is difficult. Therefore, it is difficult to recommend the optimal method. The choice of mobilization method should be made depending on the overall treatment goals of a given patient.

Previous treatment with cytotoxic agents

.Patients with a history of active myelosuppressive therapy may not have a sufficient increase in PSCC to the recommended minimum level (at least 2.0 x 10⁶ CD34+ cells/kg) or an increased rate of platelet count normalization.

Some cytostatics are particularly toxic to hematopoietic progenitor cells and may adversely affect their mobilization. Prolonged use of drugs such as melphalan, carboplatin or carmustine before progenitor cell mobilization can lead to poorer results. However, simultaneous use of melphalan, carboplatin and carmustine with filgrastim is effective in HSCC mobilization. If HSCC transplantation is planned, it is recommended to plan their mobilization early in the patient’s treatment course. Particular attention should be paid to the number of progenitor cells activated in these patients before the use of high-dose chemotherapy. If mobilization has not resulted in sufficient numbers of PSCs, alternative therapies that do not require the use of progenitor cells should be considered.

Estimating the number of PSCs

In evaluating the number of PSCs mobilized in patients with Tevagrastim, special attention should be given to the method of quantification. The results of flow-cytometric analysis of the number of CD34+ cells vary depending on the method chosen, and therefore results from different laboratories should be interpreted with caution.

There is a complex but robust statistical relationship between the number of CD34+ cells infused in reinfusion and the rate of platelet count recovery after high-dose chemotherapy.

The minimum number of PSCCs equal to or greater than 2 x 10⁶ CD34+ cells/kg results in sufficient recovery of hematological parameters and is recommended based on published data. The number of CD34+ cells exceeding this value seems to be accompanied by a more rapid normalization; if the number of cells is less than this value, the recovery of blood parameters is slower.

Cautions for healthy donors during PSCC mobilization

Cell mobilization and apheresis procedures should be performed at a center experienced in this field.

PSCC mobilization has no immediate clinical outcome when used in healthy donors and can only be performed for the purpose of allogeneic stem cell transplantation.

PSCC mobilization can only be performed in donors who meet standard clinical and laboratory criteria for stem cell donation. Particular attention must be paid to hematological parameters and the presence of infectious diseases.

The safety and efficacy of Tevagrastim in healthy donors under 16 years of age and over 60 years have not been studied.

Transient leukocytosis (leukocytes over 50 x 10⁹ / L) was noted in 41% of patients. Transient thrombocytopenia (platelet count less than 100 x 10⁹/l) after filgrastim administration and leukapheresis was observed in 35% of donors. In addition, 2 cases of thrombocytopenia less than 50 x 10⁹/l were observed after the leukapheresis procedure.

If more than one leukapheresis procedure is required, the platelet count should be monitored particularly carefully before each apheresis procedure, especially if the platelet count is less than 100 x 10⁹/l. Leukapheresis is not recommended if the platelet count is less than 75 x 10⁹/L, if anticoagulants are used, or if there are hemostasis disorders.

The dose of Tevagrastim should be withdrawn or reduced if the white blood cell count is greater than 70 x 10⁹/L.

In healthy donors who receive G-CSF for PSCC mobilization, all clinical blood counts should be monitored regularly until they normalize.

The safety of Tevagrastim in healthy donors continues to be monitored. At this time, the risk of developing a myeloid malignant clone in donors cannot be ruled out. Medical centers performing apheresis procedures are recommended to systematically monitor stem cell donors for at least 10 years in order to monitor the safety of Tevagrastim in the long term.

There are reports of private, mostly asymptomatic cases of splenomegaly, as well as very rare cases of spleen rupture in healthy donors and patients after G-CSF infusion. Some cases of spleen rupture have been fatal. Therefore, the size of the spleen should be carefully monitored (clinical examination (palpation) and ultrasound examination). The risk of spleen rupture in donors and patients with upper left abdominal pain or upper left shoulder pain should be considered.

In the post-registration period, very rare cases of adverse effects of G-CSF on the respiratory system (hemoptysis, pulmonary bleeding, pulmonary infiltrates, shortness of breath and hypoxia) were noted in healthy donors. If these symptoms are suspected, further use of the drug and the need for appropriate treatment should be considered.

Cautions for recipients of allogeneic PSCC derived with filgrastim

Allogeneic PSCC transplantation has a higher risk of developing an acute or chronic graft versus host reaction than allogeneic bone marrow transplantation.

Cautions for patients with TCN

Blood cell count

The platelet count should be monitored carefully, especially during the first few weeks of treatment with the drug. If a patient develops thrombocytopenia (platelet count is less than 100 x 10⁹/L for a long time), temporary withdrawal of the drug or reduction of the dose should be considered.

There may be other changes in blood count that require close monitoring, including anemia and transient increase of myeloid progenitor cells.

The development of acute leukemia or MDS

Timely diagnosis of TCH and differentiation of this diagnosis from other disorders of the hematopoietic system, such as aplastic anemia, MDS and myeloleukemia, should be made. Before initiating therapy, a complete blood count and platelet count should be performed, and bone marrow morphology and karyotype should be determined.

In clinical trials, a small number (approximately 3%) of patients with TCH who received filgrastim have seen MDS and leukemia. These results were only observed in patients with congenital neutropenia (Kostman syndrome). MDS and leukemia are the most frequent complications of TCN, and their association with filgrastim treatment has not been determined. Approximately 12% of patients with initially normal cytogenetics showed abnormalities, including monosomy 7, on reexamination. If a patient with TCN manifests cytogenetic abnormalities, the ratio of expected benefit to possible risk from continued therapy with Tevagrastim should be carefully evaluated. The drug should be discontinued if MDS or leukemia develops. It is currently unclear whether long-term use of Tevagrastim induces cytogenetic abnormalities, MDS or leukemia in patients with TCN. Morphologic and cytogenetic studies of the bone marrow are recommended regularly (approximately 12 months later).

Long-term (>5 years) use of filgrastim has been associated with cytogenetic abnormalities, leukemia, and osteoporosis in 9.1% of patients with TCHN. An association with filgrastim use has not been established.

Other precautions

The causes of transient neutropenia such as viral infections must be excluded.

Spleen enlargement is a likely effect associated with treatment with filgrastim. During clinical trials, 31% of patients showed splenomegaly on palpation. On radiography, an increase in spleen size was detected soon after treatment with filgrastim and tended to stabilize. It has been noted that reducing the dose of the drug slows or stops the increase in spleen size; splenectomy may be necessary in 3% of patients. Spleen size should be monitored regularly with clinical examination.

A small number of patients have had hematuria/proteinuria. Routine monitoring of urinalysis should be performed to exclude these manifestations.

The safety and effectiveness of the drug in neonates and patients with autoimmune neutropenia have not been established.

Cautions for patients with HIV infection

Blood cell count

The ACN must be closely monitored, especially during the first weeks of therapy with Tevagrastim. Some patients may experience a very rapid and significant increase in ACN at the initial dose of Tevagrastim. During the first 2-3 days of use it is recommended to measure ACN daily. Thereafter, the ACN should be checked at least twice a week for the first 2 weeks and then every week or every other week for the duration of maintenance therapy. If Tevagrastim is interrupted at a dose of 30 million IU/day (300 mcg/day), the patient may experience significant ACN fluctuations during treatment. In order to determine the minimum ACN (nadir) it is recommended to monitor the general blood count before each Tevagrastim infusion.

Risk of high doses of myelosuppressive drugs (MSLP)

Monotherapy with Tevagrastim is not indicated to prevent thrombocytopenia and anemia with MSLP. The risk of thrombocytopenia and anemia increases if higher doses or multiple MSLPs are used simultaneously in combination with Tevagrastim therapy. Regular monitoring using a gross blood count is recommended.

The development of myelosuppression due to infections or tumor neoplasms

.Neutropenia may be due to bone marrow damage from opportunistic infections that are caused by pathogens such as Mycobacterium avium complex or malignant neoplasms such as lymphoma. If infiltrative bone marrow lesion, inflammatory lesion or malignant neoplasm are detected, simultaneously with the use of Tevagrastim for treatment of neutropenia, the appropriate therapy of diagnosed diseases should be used. The efficacy of Tevagrastim in the treatment of neutropenia due to bone marrow lesions of infectious origin or tumor neoplasms has not been established.

Cautions for patients with sickle cell disease

Patients with sickle cell anemia have had cases of hemolytic crisis (increased number of altered cells), sometimes with a fatal outcome. Patients with sickle cell disease should use Tevagrastim only if the expected benefits exceed the possible risks with Tevagrastim.

Effects of excipients

The 50 mg/ml sorbitol contained in Tevagrastim should not adversely affect patients with hereditary fructose intolerance. However, Tevagrastim should be used with caution in these patients.

Influence on driving and operating ability

No effect of filgrastim on driving and operating ability has been noted.

Contraindications

Hypersensitivity to the drug and its components in the history; severe congenital neutropenia (Kostmann syndrome) with cytogenetic disorders; simultaneous administration with cytotoxic chemotherapy and radiation therapy; the drug should not be used to increase the doses of cytotoxic chemotherapeutic agents above the recommended doses, terminal stage of chronic renal failure; period of breastfeeding; neonatal age (up to 28 days of life).

With caution

.In pregnancy, malignant and pre-tumor diseases, patients with sickle-cell anemia, bone tissue pathology (including osteoporosis), with secondary acute myeloleukemia (due to limited data on safety and effectiveness), when treating patients receiving high-dose chemotherapy, hereditary fructose intolerance (the drug contains sorbitol).

Side effects

Side effects are categorized according to frequency of occurrence: very common (≥ 1/10); common (≥ 1/100, but < 1/10); infrequent (≥ 1/1000, but < 1/100); rare (≥ 1/10000, but < 1/100); very rare (< 1/10000); unknown frequency (cannot be determined based on available data).

Patients with cancer

.The most common adverse effects associated with the use of filgrastim at the recommended dose were mild to moderate musculoskeletal pain (in 10% of patients) and severe musculoskeletal pain (in 3% of patients). Musculoskeletal pain was usually managed with standard analgesic treatment. Less frequent adverse effects were urinary disorders (mostly mild to moderate dysuria).

Filgrastim did not increase the frequency of adverse reactions associated with cytotoxic chemotherapy. Undesirable effects were observed with equal frequency in patients using filgrastim/chemotherapy and placebo/chemotherapy, including nausea and vomiting, alopecia, diarrhea, fatigue, lack of appetite, mucosal inflammation (mucositis), headache, cough, skin rash, chest pain, general weakness, sore throat, constipation and nonspecific pain.

Abstract, dose-dependent and usually mild to moderate increase in lactate dehydrogenase (LDH), alkaline phosphatase (ALP), uric acid concentration and plasma gamma-glutamyl transferase (GGT) activity was observed with filgrastim at the recommended doses in approximately 50%, 35%, 25% and 10% of patients, respectively.

Transient decreases in blood pressure (BP) have occasionally been observed that do not require therapeutic intervention.

Transplant versus host reaction and death have been reported in patients receiving G-CSF after allogeneic bone marrow transplantation.

Sometimes patients receiving high-dose chemotherapy followed by autologous bone marrow transplantation have reported vascular disorders, including veno-occlusive disease and disorders related to water metabolism in the body. A causal relationship with the use of filgrastim in these cases has not been established.

Very rare cases of cutaneous vasculitis have been reported in patients treated with filgrastim. The mechanism of vasculitis in patients receiving filgrastim has not been established.

There have been rare reports of Sweet’s syndrome (acute febrile dermatosis). Because a significant proportion of these patients suffered from leukemia, which is known to be associated with Sweet’s syndrome, a causal relationship with filgrastim has not been established.

In some cases an exacerbation of rheumatoid arthritis has been observed.

Pseudopodagra has been reported in patients with cancer who received filgrastim.

Rare adverse pulmonary effects have been reported, including interstitial pneumonia, pulmonary edema and pulmonary infiltrates, with a single adverse outcome of respiratory failure or adult respiratory distress syndrome (ARDS), including death.

Single cases of symptoms indicative of allergic reactions, including anaphylaxis, skin rash, urticaria, Quincke’s edema, dyspnea, decreased BP, developing during the first dose or subsequent use of filgrastim have been described. Such reactions were more frequent after intravenous administration. In some cases, symptoms recurred after repeated use of filgrastim, indicating a causal relationship. The use of filgrastim should be discontinued in patients who have developed severe allergic reactions.

Some cases of sickle cell crises have been reported in patients with sickle cell anemia.

From the immune system:very rarely, allergic reactions.

Metabolism and nutrition: very often – increased activity of LDH, ALP, increased concentration of uric acid in plasma.

Nervous system side: frequently – headache.

Vascular disorders: infrequently – syndrome of increased capillary permeability; rarely – vascular disorders, angiopathy, aortitis.

Respiratory system: frequent – cough, sore throat; very rare – lung infiltrates.

Gastrointestinal tract: very common – nausea, vomiting; frequent – constipation, diarrhea, anorexia, mucositis.

From the liver and biliary tract:very often – increased GGT activity.

Skin and subcutaneous fat: frequently – alopecia, skin rash; very rarely – Sweet’s syndrome, cutaneous vasculitis.

Skin and musculoskeletal system: frequently – chest pain, musculoskeletal pain; very rarely – exacerbation of rheumatoid arthritis.

System of the urinary system: very rarely – impaired urination.

Others:often – fatigue, general weakness; infrequently – nonspecific pain.

Healthy donors during PSCC mobilization

Transient mild to moderate musculoskeletal pain was very common.

Leukocytosis (greater than 50 x 10⁹/l) was observed in 41% of healthy donors and transient thrombocytopenia (less than 100 x 10⁹/l) after filgrastim and leukophoresis was observed in 35% of healthy donors. Transient slight increases in alkaline phosphate, LDH, aspartate aminotransferase (AST) and plasma uric acid concentrations were reported in healthy donors receiving filgrastim (without clinical consequences).

There have been rare reports of arthritis exacerbation.

Symptoms indicative of severe allergic reactions have occasionally been reported.

Headache, thought to be related to filgrastim use, has been reported in healthy donors during PSCC mobilization in studies.

Frequent, mostly asymptomatic cases of splenomegaly and very rare cases of spleen rupture have been reported in healthy donors and patients after G-CSF administration.

In healthy donors, respiratory adverse events (hemoptysis, pulmonary bleeding, pulmonary infiltrates, dyspnea and hypoxia) were very rarely observed with filgrastim in the post-registration period.

In the post-registration period, cases of increased capillary permeability syndrome have been reported with G-CSF. They were usually observed in patients with advanced malignant disease, sepsis, taking several chemotherapy drugs simultaneously or undergoing apheresis. Increased capillary permeability syndrome can be life-threatening if treatment is delayed. Infrequently (≥1/1000 to < 1/100) this syndrome has been observed in healthy donors during PSCC mobilization after G-CSF administration.

Blood and lymphatic system disorders:very frequently, leukocytosis, thrombocytopenia; infrequently, disorders of the spleen.

Immune system disorders: infrequently – severe allergic reactions.

Metabolic and nutritional disorders:often – increased activity of ALP, LDH; infrequently – increased activity of AST.

Nervous system disorders: very often – headache.

vascular disorders: infrequently – syndrome of increased capillary permeability, rarely – aortitis.

Muscular system disorders: very common – musculoskeletal pain; infrequent – exacerbation of rheumatoid arthritis.

Patients with TCHN

The incidence of adverse effects associated with filgrastim in patients with TCHN tends to decrease over time.

The most common adverse effects associated with filgrastim use have been bone and muscle pain.Spleen enlargement, progressive in some cases, and thrombocytopenia have also been observed. Headache and diarrhea were usually observed shortly after starting filgrastim treatment in less than 10% of patients. Anemia and nasal bleeding have also been reported.

Transient increases in plasma uric acid concentration, LDH activity, and ALP have been observed without clinical consequences. There was also a transient moderate decrease in blood glucose concentration after a meal.

The undesirable effects possibly associated with the use of filgrastim, and usually observed in less than 2% of patients with TCH, were injection site reactions, headache, liver enlargement, joint pain, alopecia, osteoporosis and skin rash.

During long-term use of filgrastim, cutaneous vasculitis has been reported in 2% of patients with TCHN, as well as very rare cases of proteinuria/hematuria.

Blood and lymphatic system disorders: very frequently, anemia, splenomegaly; frequently, thrombocytopenia; infrequently, disorders of the spleen.

Metabolism and nutrition:very often – decreased blood glucose concentration, increased alkaline phosphate, LDH, hyperuricemia.

Nervous system disorders: often – headache.

Breathing system side: very often – nasal bleeding.

Digestive system disorders:often – diarrhea, hepatomegaly.

Skin and subcutaneous tissue: frequent – alopecia, skin rash, cutaneous vasculitis, pain at the injection site.

Muscular system: very often – bone and muscle pain; often – osteoporosis.

Recreational and urinary tract disorders: infrequently – hematuria, proteinuria.

Patients with HIV infection

Mild to moderate musculoskeletal pain and myalgia associated with filgrastim have been consistently observed. The frequency of pain was similar to that seen in patients with cancer.

Spleen enlargement associated with filgrastim use was seen in less than 3% of patients. In all cases, mild to moderate splenomegaly with a favorable clinical course was observed on physical examination; there were no cases of hypersplenism or splenectomy.

Splenomegaly is quite common in patients with HIV infection, and is also present in varying degrees in most patients with AIDS. In these cases, the relationship of splenomegaly to the use of filgrastim remains unclear.

Blood and lymphatic system disorders:often spleen disorders.

Muscular system disorders:very often – musculoskeletal pain.

Overdose

Cases of filgrastim overdose have not been reported. Within 1-2 days after drug withdrawal, the number of circulating neutrophils usually decreases by 50% and returns to normal levels in 1-7 days.

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Pregnancy use

The safety of filgrastim for pregnant women has not been established. It may pass through the placental barrier in women. When prescribing the drug to pregnant women the expected therapeutic effect should be weighed against the possible risk to the fetus. There are no data on the penetration of filgrastim into breast milk. It is not recommended to use the drug during breast-feeding.