Neustachym, extract 10 mg/ml 0.6 ml

Pharmacodynamics

Hematopoietic growth factor. Pegfilgrastim is a covalent conjugate of filgrastim (recombinant human granulocyte colony-stimulating factor /G-CSF/), with one 20 kDa polyethylene glycol (PEG) molecule, with prolonged action due to reduced renal clearance.

Like filgrastim, pegfilgrastim regulates the formation and release of neutrophils from the bone marrow, markedly increases the number of neutrophils with normal or increased functional activity (chemotaxis and phagocytosis) in peripheral blood over 24 hours and causes a slight increase in the number of monocytes and/or lymphocytes.

Like other hematopoietic growth factors, G-CSF can stimulate endothelial cells in vitro.

A transient increase in leukocytes (leukocytosis) is an expected consequence of pegfilgrastim therapy because it is consistent with its pharmacodynamic effects. No adverse events directly related to this leukocytosis have been described.

Clinical efficacy

A single infusion of pegfilgrastim after each cycle of myelosuppressive cytostatic therapy reduces the duration of neutropenia and the incidence of febrile neutropenia similar to daily administration of filgrastim (an average of 11 daily infusions). The use of pegfilgrastim after chemotherapy has also been shown to significantly reduce the frequency of IV antimicrobial administration and hospitalization due to febrile neutropenia.

Pharmacokinetics

Absorption

After a single infusion, the Tmax of pegfilgrastim is 16-120 hr.

Distribution

The serum concentration of pegfilgrastim is maintained during the period of neutropenia following myelosuppressive chemotherapy.

The distribution of pegfilgrastim is limited to plasma.

Elevation

Elevation of pegfilgrastim is nonlinear, dose-dependent, saturable. Clearance is mainly by neutrophils ( > 99%) and decreases with increasing pegfilgrastim dose. According to the self-regulating mechanism of clearance, the serum concentration of pegfilgrastim decreases rapidly as neutrophil counts begin to recover.

Graphs of changes in median serum pegfilgrastim concentration and median absolute neutrophil count (ANC) over time after a single injection of 6 mg of pegfilgrastim in patients receiving chemotherapy.

GRAPHIC

Pharmacokinetics in special patient groups

Given the clearance involving neutrophils, it is likely that the pharmacokinetics of pegfilgrastim are not altered in renal or hepatic impairment.

The pharmacokinetics of pegfilgrastim in patients over 65 years of age are similar to those in adults.

The mean systemic AUC_0-∞ exposure of pegfilgrastim after p/k administration at a dose of 100 µg/kg in children with sarcoma aged 6-11 years was 22.0 µg×h/mL, 29.3 µg×h/mL in children 12-21 years, and 47.9 µg×h/mL in children 0-5 years. The terminal T_1/2 in children in the respective age groups was 20.2 h, 21.2 h, and 30.1 h, respectively.

Indications

To reduce the duration of neutropenia, the incidence of febrile neutropenia and infections manifested by febrile neutropenia during cytotoxic chemotherapy for malignant diseases.

Active ingredient

Pegfilgrastim

Composition

1 syringe tube contains:

The active ingredients: pegfilgrastim 6 mg.

Excipients: sodium acetate – q.s. to pH 4.0, sorbitol – 30 mg, polysorbate 20 – 0.02 mg, water d / i – to 0.6 ml.

The syringe-tube contains 0.6 ml of solution. In a plastic container 1 syringe-tube together with a sterile d/i needle. In the carton 1 plastic container.

How to take, the dosage

In adults (≥18 years of age), the drug is administered by mouth at a dose of 6 mg (1 syringe tube) 24 hours after each cycle of cytotoxic chemotherapy.

Never use Neustalim® less than 14 days before, during and less than 24 hours after administration of cytotoxic chemotherapeutic agents.

The administration of Neustalime® should be stopped if the total leukocyte count rises above 50 × 10⁹/L.

There are no recommendations for the use of Neustalam® in children and adolescents under 18 years of age (insufficient data).

Patients weighing less than 45 kg should not receive a fixed dose (6 mg) of Neustastim® (insufficient data).

Instructions for Use, Handling and Disposal

The Neustalime® syringe tube is for single use only.

The Neustalaim® product is a sterile, preservative-free solution.

The Neustalime® solution should be inspected for foreign visible particles prior to administration. Only a clear and colorless solution may be injected.

Excessive shaking can destroy pegfilgrastim, rendering it biologically inactive.

The solution in the syringe tube should be warmed to room temperature before injection.

Any unused product or residue should be disposed of in accordance with sanitary requirements.

The release of medication into the environment should be kept to a minimum. The drug should not be disposed of with wastewater or with household waste. If possible, special systems should be used to dispose of medications.

Interaction

Cytotoxic chemotherapy: Due to the possible sensitivity of rapidly dividing myeloid cells to cytotoxic therapy Neulastim® should be administered 24 h after the administration of cytotoxic chemotherapeutic agents. In clinical trials, the drug was safely administered 14 days before the introduction of cytotoxic chemotherapeutic agents.

Fluorouracil or other antimetabolites: increased suppression of hematopoiesis in vivo (in animals). Interaction with other hematopoietic growth factors and cytokines is unknown.

The possibility of interaction with lithium, which also promotes neutrophil release, has not been specifically investigated. There is no confirmation that this interaction could be harmful.

There have been no studies on specific interactions or metabolism.

The safety and efficacy of Neustalime® in patients receiving chemotherapy leading to delayed myelosuppression (e.g., nitrosourea derivatives) has not been studied.

There are currently no signs of interaction of Neustachym® with other medicinal products.

Incompatibilities

Neustalime® is incompatible with sodium chloride solutions.

Special Instructions

Treatment with Neulasticum® should only be performed under the supervision of an oncologist or hematologist experienced in the use of G-CSF.

Limited data suggest that the efficacy of pegfilgrastim and filgrastim is similar with respect to the time to resolution of severe neutropenia in patients with de novo acute myeloleukemia. However, caution should be exercised with Neulastim® therapy in patients with de novo acute myeloleukemia, as long-term results of such therapy have not been established.

G-CSF stimulates endothelial cells and may accelerate growth of myeloid cells, including malignant cells, and some nonmyeloid cells in vitro. Neustalim® should not be used in myelodysplastic syndromes, chronic myeloleukemia, and secondary acute myeloleukemia because safety and efficacy have not been evaluated in these patient groups. The differential diagnosis between blast transformation in chronic myeloleukemia and acute myeloleukemia should be particularly careful.

The safety and efficacy of Neustalim® in patients with de novo acute myeloleukemia younger than 55 years of age with t translocation (15;17) have not been studied.

The safety and efficacy of Neulastim® in patients treated with high-dose chemotherapy have not been studied.

Cough, fever, and dyspnea combined with radiologic infiltrative changes, impaired lung function, and increased neutrophil counts may be signs of adult respiratory distress syndrome. In this case, Neustalim® should be discontinued at the discretion of the physician and appropriate treatment administered.

There have been very rare cases of spleen rupture after the use of pegfilgrastim, some with a fatal outcome. The size of the spleen should be closely monitored by instrumental examination (ultrasound). The possibility of splenomegaly or rupture of the spleen in patients with complaints of upper left abdominal pain and/or upper left shoulder should be considered.

Monotherapy with Neustalim® does not preclude thrombocytopenia and anemia if full-dose myelosuppressive chemotherapy is continued. It is recommended that platelet count and hematocrit be determined regularly.

Nealastim® should not be used to increase cytotoxic chemotherapy doses above those established in the dosing regimens.

The development of sickle cell crisis has been associated with pegfilgrastim therapy in patients with sickle cell anemia. Therapy with pegfilgrastim in patients with sickle cell anemia should be used with caution only after careful determination of potential risk and benefit.

The leukocytosis of 100 × 10⁹/L or more is seen in less than 1% of patients receiving Neustastim®, is temporary, and is usually seen 24-48 h after administration, consistent with the pharmacodynamic effects of the drug. No adverse events directly related to such leukocytosis have been described.

The safety and efficacy of pegfilgrastim in peripheral blood stem cell mobilization in patients have not been appropriately evaluated.

The increased hematopoietic bone marrow activity in response to growth factor therapy leads to transient positive changes in bone imaging, which should be taken into account when interpreting results.

In a clinical study in children, bone pain was the most common adverse event as in adults.

The effect of Neustalim® on the ability to drive vehicles and other mechanisms requiring high concentration

There have been no studies of the effect of Neustalim® on the ability to drive vehicles and to perform potentially dangerous activities requiring high concentration and quick psychomotor reactions.

Contraindications

• Neutropenia in chronic myeloleukemia and myelodysplastic syndromes;
• acute leukemia;
• to increase doses of cytotoxic chemotherapy above those established in the dosing regimen;
• prescribing cytotoxic chemotherapyconcomitant administration with cytotoxic chemotherapy and radiation therapy;
• pregnancy;
• breastfeeding period;
• age under 18 years of age;
• hypersensitivity to proteins derived from E. coli, filgrastim, pegfilgrastim or any other component of the drug.

With caution: The drug should be used in malignant and pre-tumor diseases of a myeloid nature (including acute myeloid leukemia.

Cautions: The preparation should be used in combination with high-dose chemotherapy; in sickle cell anemia and in case of hereditary fructose intolerance (contains sorbitol).

Side effects

The following categories are used to estimate the frequency of side effects:

• very frequently (≥10%);
• often (≥1%, < 10%);
• infrequently (≥0.1%, < 1%);
• rarely (≥0.01%, < 0.1%);
• very rarely ( < 0.01%, including isolated cases).

Clinical trial data

In patients receiving Neulastim® after cytotoxic chemotherapy, most adverse events were due to the underlying malignant disease or cytotoxic chemotherapy.

Mild to moderate bone pain was very frequently reported with the use of the drug, which in most cases resolved on its own or was managed with non-narcotic analgesic agents.

Skeletal-muscular system and connective tissue disorders: very often – bone pain; often – arthralgia, myalgia, musculoskeletal pain, back, limb and neck pain.

General disorders and disorders at the injection site: often – pain and erythema at the injection site, chest pain (noncardiac), pain.

Nervous system disorders: often – headache.

Blood and lymphatic system disorders: infrequent – leukocytosis.

Gastrointestinal disorders: nausea (frequency unknown).

Laboratory parameters: very common – reversible, mild to moderate clinically insignificant increase in the activity of ALP and LDH; common – reversible, mild to moderate clinically insignificant increase in uric acid.

Post-registration use of the drug

Immune system disorders: rare – anaphylaxis, rash, urticaria, angioedema, dyspnea and arterial hypotension, erythema and hyperemia at the beginning of therapy or during subsequent administration of the drug. Sometimes resumption of treatment is accompanied by relapse of symptoms. If serious allergic reactions develop, appropriate treatment should be prescribed with careful monitoring of the patient for several days. Therapy with pegfilgrastim should be discontinued if serious allergic reactions develop.

Gastrointestinal disorders: pain in the upper left abdomen (frequency unknown).

Blood and lymphatic system disorders: very rare – rupture of the spleen (in some cases with fatal outcome), splenomegaly (frequency unknown), vasoocclusive crisis (frequency unknown).

Respiratory system, chest and mediastinal organs: cough (frequency unknown), dyspnea (frequency unknown), pulmonary infiltrates (frequency unknown), respiratory dysfunction (frequency unknown), respiratory distress syndrome (frequency unknown).

General disorders and disorders at the site of administration: fever (frequency unknown).

Skin and subcutaneous fatty tissue disorders: rare – Sweet’s syndrome (acute febrile dermatosis); cutaneous vasculitis (estimated frequency of reports 0.00038%).

Overdose

Single oral doses of 300 mcg/kg did not cause serious adverse events in healthy volunteers or in patients with non-small cell lung cancer. Overdose adverse events did not differ from those of normal drug administration at the recommended doses.