Granocite^® 34 (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Chugai Sanofi-Aventis (France)

Manufactured By

Sanofi Winthrop Industrie (France)

ATC Code

L03AA10 (Lenograstim)

Active Substance

Lenograstim (Rec.INN registered by WHO)

Dosage Form

Granocyte® 34

Lyophilisate for preparation of solution for intravenous and subcutaneous administration 33.6 million IU: vial 5 pcs. in set with solvent

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for intravenous and subcutaneous administration white in color.

Excipients: mannitol (D-mannitol), polysorbate 20, arginine (L-arginine), phenylalanine (L-phenylalanine), methionine (L-methionine), hydrochloric acid.

Solvent water for injections – 1 ml.

Colorless glass vials (5) in a set with solvent (amp. 5 pcs.) – contour plastic packaging (1) – cardboard packs.

Clinical-Pharmacological Group

Leukopoiesis stimulant

Pharmacotherapeutic Group

Leukopoiesis stimulator

Pharmacological Action

Recombinant human glycosylated granulocyte colony-stimulating factor (G-CSF) belongs to the group of cytokines, biologically active proteins that regulate cell differentiation and proliferation.

G-CSF is a factor that stimulates the precursor cells of the neutrophil lineage of the bone marrow. Granocyte^® 34 causes a marked increase in the number of neutrophils in the peripheral blood, which is dose-dependent in the dose range of 1-10 mcg/kg/day. Repeated administration of the drug in recommended doses causes an additional increase in the neutrophil count in the blood.

Neutrophils produced in response to the administration of Granocyte 34 have normal chemotactic properties and phagocytic activity. G-CSF is capable of stimulating the proliferation of human endothelial cells.

The use of Granocyte 34, both after chemotherapy and independently of it, leads to the mobilization (release) of hematopoietic progenitor cells into the peripheral blood, which can be isolated from the blood and administered intravenously to the patient after high-dose chemotherapy to restore damaged hematopoiesis instead of or in addition to bone marrow transplantation.

It has been shown that the administration of autologous hematopoietic progenitor cells from the peripheral blood, obtained by stimulation with Granocyte 34, to the patient promotes faster recovery of hematopoiesis compared to autologous bone marrow transplantation, which also significantly reduces the duration of thrombocytopenia.

Pharmacokinetics

The pharmacokinetic parameters of Granocyte 34 depend on the dose of the drug and the duration of its administration. There is a direct relationship between the dose and plasma concentration of lenograstim and between the neutrophil response and the plasma concentration of lenograstim.

Absorption

With repeated administration (IV and SC), C_max is proportional to the administered dose; no accumulation of the drug was detected. When used in recommended doses, the absolute bioavailability of the drug is 30%.

Distribution

The mean residence time in the body after SC administration is 7 hours.

Metabolism

Lenograstim is biotransformed into peptides.

Elimination

T_1/2 after SC administration is 3-4 hours, after repeated IV administration – 1-1.5 hours. Less than 1% of the administered dose is excreted unchanged in the urine.

Indications

• To shorten the period of neutropenia and its associated complications (in patients with non-myeloproliferative neoplasms who have undergone myelosuppressive therapy followed by bone marrow transplantation, and in those at high risk of developing prolonged severe neutropenia);
• To reduce the duration of severe neutropenia and its associated complications after standard myelosuppressive chemotherapy;
• For mobilization of peripheral hematopoietic progenitor cells in the peripheral blood.

ICD codes

Dosage Regimen

The drug is administered subcutaneously or intravenously by drip over 30 minutes.

For bone marrow transplantation, standard cytotoxic chemotherapy, and for mobilization of hematopoietic progenitor cells in the peripheral blood after the use of cytostatics, the drug is prescribed at a dose of 150 mcg (19.2 million IU)/m² of body surface area/day, which is equivalent to 5 mcg (0.64 million IU)/kg body weight/day. Administration of the drug begins on the day after bone marrow transplantation or completion of chemotherapy. The drug is administered daily subcutaneously (in bone marrow transplantation, it can be administered as a 30-minute intravenous infusion) until, after the expected decrease in the white blood cell count, their number is restored to a normal level, upon reaching which the drug can be discontinued. The maximum duration of daily administration of the drug is 28 days.

For mobilization of hematopoietic progenitor cells in the peripheral blood without the use of cytostatics, the recommended dose of the drug is 10 mcg (1.28 million IU)/kg body weight/day, administered subcutaneously daily for 4-6 days.

Leukapheresis should be performed after the white blood cell count has recovered or after CD34⁺ cells have been detected in the blood using conventional methods. In patients who have not previously received massive chemotherapy, one leukapheresis is often sufficient to obtain the minimum required number of cells (≥ 2×10⁶ CD34⁺ cells/kg body weight).

In healthy donors, administration of the drug subcutaneously for 5-6 days at a dose of 10 mcg (1.28 million IU)/kg body weight allowed obtaining ≥3×10⁶ CD34⁺ cells/kg body weight as a result of one leukapheresis in 83% of cases and as a result of two leukaphereses in 97% of cases.

No special studies have been conducted in elderly patients. Therefore, there are no recommendations for changing the dosage regimen in elderly patients.

The safety and efficacy of Granocyte^® 34 in bone marrow transplantation have been established in children over 2 years of age.

Rules for preparation of the injection solution

To prepare the solution for subcutaneous administration, the contents of the vial are dissolved in 1 ml of the supplied solvent, gently mixing (do not shake vigorously) for about 5 seconds.

For intravenous use, the resulting solution should be further diluted with 0.9% sodium chloride solution or 5% dextrose solution to a concentration of at least 0.32 million IU/ml (2.5 mcg/ml), but not more than 100 ml of the above solutions.

The reconstituted solution should be stored at a temperature of 2°C (35.6°F) to 8°C (46.4°F) for 24 hours. The prepared solution should be used as soon as possible.

Adverse Reactions

When using Granocyte 34 in healthy individuals, the most frequently occurring side effects were headache in 30%, bone pain in 23%, lower back pain in 17.5%, asthenia in 11%, and abdominal pain in 6% of cases. The risk of pain was higher in individuals with high white blood cell counts, especially if the white blood cell count exceeded 50,000/μl (observed in 24% of donors), and apheresis-associated thrombocytopenia (platelet count less than 100,000/μl) was observed in 42% of donors. A transient increase in AST and/or ALT levels was observed in 12%, and a transient increase in alkaline phosphatase levels in 16% of donors.

Side effects observed during bone marrow transplantation, such as infectious and inflammatory lesions of the oral cavity, fever, diarrhea, abdominal pain, vomiting, rash, alopecia, sepsis and infections, are associated with conditioning regimens and not with the use of Granocyte 34. The effect of Granocyte 34 on the frequency and severity of acute and chronic graft-versus-host disease has not been reliably determined.

Special attention during bone marrow transplantation should be paid to monitoring the platelet count in the peripheral blood, as their level when using the drug may be lower than usual.

When using Granocyte 34 for chemotherapy-induced neutropenia, side effects characteristic of cytostatic drugs are usually observed. Bone pain and injection site reactions (redness, swelling) were noted somewhat more frequently. Infrequently, reports of pulmonary infiltrates appeared, which in several cases led to the development of pulmonary insufficiency or distress syndrome in adults.

If symptoms such as cough, fever, and shortness of breath appear during the use of Granocyte 34, combined with radiological changes and respiratory dysfunction, appropriate therapy should be prescribed and the question of discontinuing Granocyte 34 should be considered.

In very rare cases, various allergic reactions were noted, extremely rarely with the development of anaphylactic shock. Extremely rare cases of vasculitis, erythema nodosum, pyoderma, Lyell’s syndrome were noted.

Common, but mostly asymptomatic, cases of spleen enlargement and very rare cases of spleen rupture have been reported in healthy donors or patients after administration of G-CSF.

Contraindications

• Myeloid neoplasms (except for newly diagnosed acute myeloblastic leukemia);
• Newly diagnosed acute myeloblastic leukemia in patients under 55 years of age in the presence of favorable cytogenetic prognostic signs;
• Pregnancy;
• Lactation period (breastfeeding);
• Hypersensitivity to lenograstim or other components of the drug.

Use in Pregnancy and Lactation

The use of Granocyte 34 is contraindicated during pregnancy.

If it is necessary to use the drug during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

To date, the efficacy and safety of Granocyte 34 in patients with severe hepatic impairment have not been studied.

Use in Renal Impairment

To date, the efficacy and safety of Granocyte 34 in patients with severe renal impairment have not been studied.

Pediatric Use

The safety and efficacy of Granocyte^® 34 in bone marrow transplantation have been established in children over 2 years of age.

Geriatric Use

No special studies have been conducted in elderly patients. Therefore, there are no recommendations for changing the dosage regimen in elderly patients.

Special Precautions

Treatment with Granocyte 34 should be carried out under the supervision of a physician experienced in the use of cytostatic therapy.

G-CSF is capable of enhancing the growth of myeloid tumor cells in vitro; a similar effect in vitro may also be manifested on some non-myeloid tumor cells.

The efficacy and safety of Granocyte 34 in myelodysplastic syndrome, secondary acute myeloblastic leukemia or chronic myeloid leukemia have not been established. Therefore, Granocyte^® 34 should not be prescribed to patients with the above pathologies. Special attention is required when diagnosing acute myeloblastic leukemia. This diagnosis must be clearly differentiated from the blast crisis of chronic myeloid leukemia.

The effect of Granocyte 34 on the progression of myelodysplastic syndrome and its transformation into myeloid leukemia has not been established. Granocyte^® 34 should be used with extreme caution in all pre-tumor lesions of the myeloid lineage of the bone marrow. Since some tumors may, as an exception, have a G-CSF receptor, caution should be exercised in case of an unexpected tumor relapse during treatment with human G-CSF.

When the drug was administered at a dose of 5 mcg/kg/day (0.64 million IU/kg/day) in bone marrow transplantation, in no case did the white blood cell count exceed 50,000/μl. In less than 5% of cases when using the drug Granocyte^® 34 at a dose of 5 mcg/kg/day (0.64 million IU/kg/day) and cytotoxic chemotherapy, the white blood cell count was equal to or exceeded 70,000/μl. In this case, no side effects directly related to leukocytosis were observed.

Due to the potential risk associated with the occurrence of severe leukocytosis, the white blood cell count in the blood should be regularly monitored during treatment with Granocyte 34. If the white blood cell count reaches 50,000/μl, the use of Granocyte 34 should be discontinued immediately.

During the use of Granocyte^® 34 for the mobilization of hematopoietic progenitor cells in the peripheral blood, the drug should not be administered if the white blood cell count increases above 70,000/μl.

Special attention during bone marrow transplantation should be paid to monitoring the platelet count in the peripheral blood, as their level when using Granocyte 34 may be lower than usual.

Granocyte^® 34 should not be used to reduce established intervals between chemotherapy courses and/or to increase the doses of chemotherapeutic drugs, since Granocyte^® 34 only reduces myelotoxicity and does not affect other side effects of cytostatics.

Due to the increased sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, the use of Granocyte 34 is not recommended later than 24 hours before and earlier than 24 hours after the end of chemotherapy.

The mobilization of hematopoietic progenitor cells in the peripheral blood when using Granocyte 34 after chemotherapy is higher compared to the use of Granocyte 34 alone. However, the choice between the two mobilization methods should be made individually for each patient, taking into account all treatment goals.

In patients who have undergone massive myelosuppressive therapy and/or radiation therapy, the mobilization of hematopoietic progenitor cells in the peripheral blood may be insufficient to obtain the minimum required number of cells and, consequently, the restoration of hematopoiesis may be inadequate.

In patients with a significant reduction in the number of stem cells in the bone marrow (due to previous intensive radiation or chemotherapy), the neutrophil response may sometimes be reduced; the safety of using Granocyte^® 34 in such cases has not been established.

The program of hematopoietic progenitor cell transplantation should be planned at the early stages of the patient’s course treatment, and special attention should be paid to the number of mobilized hematopoietic progenitor cells in the peripheral blood before the use of high-dose chemotherapy. If the number of cells obtained is small, hematopoietic progenitor cell transplantation should be replaced by other treatment methods.

Since the results of CD34⁺ cell determination assays performed by flow cytometry differ in different laboratories, special attention should be paid to the methods of quantitative determination of the obtained progenitor cells.

Based on published data, achieving a minimum required number of CD34⁺ cells >2.0×10⁶ per kg of body weight is recommended for adequate restoration of hematopoiesis.

Since the mobilization of cells in the peripheral blood does not provide direct benefit to healthy donors, this procedure should be carried out in accordance with the rules for bone marrow transplantation established by law. The efficacy and safety of Granocyte^® 34 in the group of donors over 60 years of age have not been evaluated. In this regard, the use of the drug for the collection of hematopoietic progenitor cells is not recommended in this age group of donors. The procedure of hematopoietic progenitor cell mobilization should also not be performed in persons under 18 years of age.

The procedure of hematopoietic progenitor cell mobilization should be performed only in donors whose clinical and laboratory test results are suitable for bone marrow donation.

Leukapheresis should not be performed on donors who are taking anticoagulants or have hemostasis disorders. If more than one leukapheresis is required, special attention should be paid to those donors whose platelet count before leukapheresis was 100,000/μl.

In general, leukapheresis should not be performed with a platelet count of <75,000/μl. If possible, the placement of a central venous catheter should be avoided.

According to long-term follow-up data (duration up to 6 years) of donors, no serious complications were identified. Despite this, there is a possible risk of stimulation of malignant clones of myeloid cells. In this regard, it is recommended to conduct systematic monitoring of these individuals with appropriate documentation in leukapheresis centers.

Transplantation of allogeneic hematopoietic progenitor cells mobilized by Granocyte 34 may be accompanied by an increased risk of developing chronic graft-versus-host disease. Data on long-term follow-up of graft function are scarce.

To date, the efficacy and safety of Granocyte 34 in patients with severe hepatic and renal impairment have not been studied.

In humans, the use of the drug at doses up to 40 mcg/kg/day was not accompanied by the appearance of toxic side effects, except for bone and muscle pain. Discontinuation of treatment with Granocyte 34 usually leads to a 50% reduction in the number of neutrophils in the peripheral blood within 1-2 days, then this indicator returns to normal within 1-7 days. An increase in the white blood cell count on the fifth day of treatment to 50,000/μl is observed in every third patient receiving Granocyte^® 34 at the maximum dose of 40 mcg/kg/day (5.12 million IU/kg/day).

After the administration of G-CSF to healthy donors or patients, cases of spleen enlargement, mostly asymptomatic, and extremely rare cases of its rupture have been noted, in connection with which it is recommended to carefully monitor the size of the spleen (physical examination, ultrasound). If pain appears in the upper left half of the abdominal cavity and under the scapula, the possibility of spleen rupture should be excluded.

Overdose

Effects occurring with an overdose of the drug Granocyte^® 34 have not been studied.

Drug Interactions

Possible interactions of the drug Granocyte^® 34 with other hematopoietic stimulating factors and cytokines have not been studied in clinical trials to date.

Storage Conditions

List B. The drug should be stored out of the reach of children at a temperature between 2°C (35.6°F) and 25°C (77°F); do not freeze.

Shelf Life

The shelf life is 2 years.

The stability of the drug is not compromised by short-term exposure of the vials to temperatures up to 30°C (86°F) (for no more than 14 days).

Granocyte^® 34 remains stable for 24 hours after being diluted to a concentration of not less than 0.32 IU/ml (2.5 µg/ml) and when the diluted solution is stored at a temperature between 5°C (41°F) and 25°C (77°F).

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.