Neuralim® (Neulastim®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substancePegfilgrrastimPegfilgrrastim
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  • Neuralim®
    solution PC 
    Hoffmann-La Roche Ltd.     Switzerland
    • Dosage form: & nbsphypodermic solution
    Composition:

    1 syringe tube (0.6 ml) contains:

    active substance: pegfilgrastim - 6 mg;

    Excipients: sodium acetate - q.s. up to pH 4,0, sorbitol - 30 mg, polysorbate 20 - 0,02 mg, water for injections - up to 0,6 ml.

    Description:

    Transparent colorless liquid.

    Pharmacotherapeutic group:ejkopoeza stimulant
    ATX: & nbsp

    L.03.A.A   Colony-stimulating factors

    L.03.A.A.13   Pegfilgrrastim

    Pharmacodynamics:

    The mechanism of action

    Hematopoietic growth factor

    Pegfilgrastim is a covalent filgrastim conjugate (recombinant human granulocyte colony-stimulating factor [G-CSF]) with one 20-kDa polyethylene glycol (PEG) molecule, with a prolonged effect as a result of decreased renal clearance.

    Similarly filgrastimu, 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 the peripheral blood for 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.

    Transient increase in leukocytes (leukocytosis) is an expected consequence of pegfilgrastim therapy, corresponds to its pharmacodynamic effects. There are no side effects directly associated with such leukocytosis, not described.

    Clinical efficacy

    A single administration pegfilgrastima after each cycle myelosuppressive cytostatic therapy reduces the duration of neutropenia and the incidence of febrile neutropenia similar daily administration of filgrastim (average 11 daily administrations). It is also shown that the use pegfilgrastima after chemotherapy significantly reduces the incidence of intravenous antimicrobials and hospitalization for febrile neutropenia.

    Pharmacokinetics:

    Suction

    After a single subcutaneous administration, the time to reach the maximum concentration (TmOh) pegfilgrastima 16-120 h.

    Distribution

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

    The distribution of pegfilgrastim is limited by plasma.

    Excretion

    The derivation of pegfilgrastima is nonlinear, dose-dependent, saturable.Clearance is mainly carried out by neutrophils (> 99%) and decreases with increasing dose of pegfilgrastim. In accordance with a self-regulating mechanism of clearance, the concentration of pegfilgrastim in the serum rapidly decreases with the onset of recovery of the number of neutrophils.

    Graphs of median changes in pegfilgrastim concentration in blood serum and median absolute number of neutrophils (AChN) in time after a single injection of 6 mg pegfilgrastim to patients receiving chemotherapy (see Figure 1).

    Pharmacokinetics in specific patient groups

    Given the clearance with neutrophils, it is likely that the pharmacokinetics of pegfilgrastim does not change with renal or hepatic insufficiency.

    Elderly age

    The pharmacokinetics of pegfilgrastim in patients older than 65 years is similar to the pharmacokinetics in adults.

    Children

    Average System Exposure AUC0-∞ pegfilgrastim after subcutaneous administration at a dose of 100 mcg / kg in children with sarcoma aged 6-11 years was 22.0 mcg / ml, in children 12-21 years - 29.3 mcg / ml, in children 0- 5 years - 47.9 μg-h / ml. The terminal elimination half-life in children in the respective age groups was 20.2 hours, 21.2 hours and 30.1 hours, respectively.

    Indications:

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

    Contraindications:

    Hypersensitivity to proteins obtained using E.coli, filgrastim, pegfilgrastimu or to any other component of the drug.

    Neutropenia in chronic myelogenous leukemia and myelodysplastic syndromes.

    Acute leukemia.

    To increase the doses of cytotoxic chemotherapy is higher than those established in dosing regimens.

    Simultaneous administration with cytotoxic chemo- and radiotherapy.

    Pregnancy and the period of breastfeeding.

    Age to 18 years.

    Carefully:

    Malignant and premalignant diseases of a myeloid nature (including acute myelogenous leukemia de novo and secondary).

    In combination with high-dosage chemotherapy.

    Sickle-cell anemia.

    Hereditary intolerance to fructose (as part of the sorbitol).

    Pregnancy and lactation:

    Pregnancy

    Studies in pregnant women have not been conducted.

    With subcutaneous administration of pegfilgrastim to pregnant rats, no negative effect on the offspring was detected. With subcutaneous administration of low doses of pegfilgrastim, rabbits showed signs of embryo-fetotoxic action (death of the embryo). Pegfilgrrastim penetrates the placenta of rats. The potential risk associated with influencing an embryo or human fetus is unknown.

    Breastfeeding period

    Studies in lactating women have not been carried out, so Neolastim® should not be used during breastfeeding.

    Dosing and Administration:

    Adults (≥18 years old): subcutaneously, 6 mg (one syringe tube) 24 hours after each cycle of cytotoxic chemotherapy.

    Do not apply Neurastim ® less than 14 days before, during, and less than 24 hours after the administration of cytotoxic chemotherapeutic agents.

    It is necessary to cancel the administration of Neulastim® with an increase in the total number of leukocytes above 50x109/ l.

    Special patient groups

    Children: recommendations for the use of the drug Neulastim ® in children and adolescents under the age of 18 years are not (not enough data).

    Patients weighing less than 45 kg A fixed dose (6 mg) of Neulastim® (insufficient data) should not be given.

    Instructions for use, handling and destruction

    The Syringe tube with Neulastim® is for single use only.

    Neulastim® is a sterile solution with no preservatives.

    Before administration, the Neulastim® solution should be examined for visible foreign particles. It is allowed to introduce only a clear and colorless solution. Excessive shaking can destroy pegfilgrastim, making it biologically inactive.

    Before injection, the solution in a syringe tube should be warmed to room temperature.

    Any unused product or its residues should be destroyed in accordance with sanitary requirements.

    The presence of drugs in the environment should be minimized. Do not dispose of the product with sewage or with household waste. If possible, it is necessary to use special systems for the disposal of medicinal products.

    Side effects:

    To assess the frequency of side effects, the following categories are used: very often (≥10%); often (≥1%, <10%); infrequently (≥0.1%, <1%); rarely (≥0.01%, <0.1%); very rarely (<0.01%, including individual cases).

    Clinical Trials Data

    In patients receiving Neurastim® after cytotoxic chemotherapy, most of the adverse events were due to a major malignant disease or cytotoxic chemotherapy.

    Very often, when using the drug, it was reported that mild or moderate pains in the bones, which in most cases passed independently or were stopped by non-narcotic analgesics.

    From the musculoskeletal system and connective tissue: very often - pain in the bones; often - arthralgia, myalgia, musculoskeletal pain, back pain, limb and neck.

    General disorders and disorders at the site of administration: often - pain and erythema at the injection site, chest pain (non-cardial), pain.

    From the nervous system: often a headache.

    On the part of the blood and lymphatic system: infrequently - leukocytosis.

    From the gastrointestinal tract: nausea (frequency unknown).

    From the laboratory indicators: very often - a reversible, weak or moderate clinically insignificant increase in the activity of alkaline phosphatase and lactate dehydrogenase; often - reversible,a weak or moderate clinically insignificant increase in uric acid.

    Post-marketing application of the drug

    From the immune system: rarely - anaphylaxis, rash, hives, angioedema, dyspnea and arterial hypotension, erythema and hyperemia at the beginning of therapy or with subsequent administration of the drug. Sometimes the resumption of treatment is accompanied by a relapse of symptoms. If serious allergic reactions develop, appropriate treatment should be prescribed with careful monitoring of the patient for several days. It is necessary to stop pegfilgrastim therapy with the development of serious allergic reactions.

    From the gastrointestinal tract: pain in the upper left side of the abdomen (frequency unknown).

    From the side of the blood and lymphatic system: very rarely - rupture of the spleen (in some cases with a fatal outcome), splenomegaly (frequency unknown), vaso-occlusive crisis (frequency unknown).

    From the respiratory system, chest and mediastinum: cough (frequency unknown), dyspnea (frequency unknown), pulmonary infiltrates (frequency unknown), impaired breathing function (frequency unknown), respiratory distress syndrome (frequency unknown).

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

    From the skin and subcutaneous fat: rarely - Sweet syndrome (acute febrile dermatosis); Skin vasculitis (estimated frequency of reports is 0.00038%).

    Overdose:

    With a single subcutaneous injection of the drug at a dose of 300 mcg / kg of serious adverse events did not have any in healthy volunteers or patients with non-small cell lung cancer. Side effects during an overdose did not differ from side effects when the drug was administered in the recommended doses.

    Interaction:

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

    Fluorouracil or other antimetabolites. Increased oppression of hematopoiesis in vivo (in animals). Interaction with other hematopoietic growth factors and cytokines is not known.

    The ability to interact with lithium, which also promotes the release of neutrophils, has not been specifically investigated. There is no confirmation that this interaction can be dangerous.

    Studies devoted to specific interactions or metabolism were not conducted.

    The safety and efficacy of Neulastim® in patients receiving chemotherapy resulting in delayed myelosuppression (for example, drugs from the group of nitrosourea derivatives) has not been studied.

    Signs of the drug Neulastim® interaction with other drugs have not been fixed to date.

    Incompatibility

    Neutral is incompatible with solutions of sodium chloride.

    Special instructions:

    Treatment with Neulastim® should only be performed under the supervision of an oncologist or hematologist who has experience with G-CSF.

    Limited data suggest that the efficacy of pegfilgrastim and filgrastim is the same with respect to the time to stop severe neutropenia in patients with acute myeloid leukemia de novo (see section "Pharmacological properties"). However, caution should be exercised when using Neulastim® in patients with acute myelogenous leukemia de novo, Because long-term results of such therapy are not established.

    G-CSF stimulates endothelial cells and can accelerate the growth of myeloid cells, including malignant cells, and some non-myeloid cells in vitro.

    Neuralast® should not be used in myelodysplastic syndromes, chronic myelogenous leukemia, secondary acute myelogenous leukemia, since the safety and efficacy of the drug in these patient groups were not assessed. Especially careful differential diagnosis between blasttransformation in chronic myelogenous leukemia and acute myeloid leukemia.

    Safety and efficacy of Neulastim® in patients with acute myelogenous leukemia de novo younger than 55 with translocation t (15; 17) have not been studied.

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

    Cough, fever and shortness of breath, combined with radiographic infiltrative changes, impaired lung function, and an increase in the number of neutrophils may serve as signs of respiratory distress syndrome in adults. In this case, at the discretion of the doctor, Neulastim® should be withdrawn and appropriate treatment prescribed.

    Very rare cases of rupture of the spleen after the application of pegfilgrastim, some with a fatal outcome, are recorded. You should carefully monitor the size of the spleen with an instrumental examination (ultrasound). The possibility of splenomegaly or rupture of the spleen should be considered in patients with complaints of pain in the upper left part of the abdomen and / or in the upper part of the left shoulder.

    Monotherapy with Neulastim® does not exclude the development of thrombocytopenia and anemia with continued myelosuppressive chemotherapy in a full dose. It is recommended to regularly determine the number of platelets and hematocrit.

    Neuralim® should not be used to increase the doses of cytotoxic chemotherapy above those set in dosing regimens.

    The development of sickle cell crises was associated with pegfilgrastim therapy in patients with sickle cell anemia. Pagfilgrastim therapy in patients with sickle cell anemia should be conducted with caution only after a careful assessment of the potential risk and benefit.

    Leukocytosis 100x109/ l or more is observed in less than 1% of patients receiving Neulastim®,is temporary and usually observed 24-48 hours after the administration of the drug in accordance with its pharmacodynamic effects. There are no side effects directly associated with such leukocytosis, not described.

    The safety and efficacy of pegfilgrastim in the mobilization of peripheral blood stem cells in patients were not appropriately evaluated.

    The increased hematopoietic activity of the bone marrow in response to therapy with growth factors leads to transient positive changes in the visualization of the bones, which should be taken into account when interpreting the results.

    In a clinical study among children among undesirable phenomena, most often, as in adults, there was bone pain.

    Effect on the ability to drive transp. cf. and fur:

    Studies on the effect of Neulastim® on the ability to drive vehicles and engage in potentially dangerous activities that require increased concentration and speed of psychomotor reactions have not been carried out.

    Form release / dosage:

    Solution for subcutaneous administration, 6 mg / 0.6 ml.

    Packaging:

    At 6 mg / 0.6 ml in a syringe tube, the body of which is made of glass (hydrolytic class 1 according to EF), the piston is made of plastic, with a stopper made of butyl rubber, laminated

    fluoropolymer. On the other hand, the syringe tube is capped with a tip of butyl rubber laminated with fluoropolymer. 1 sterile needle for injection in a tube of polyethylene, hermetically sealed aluminum foil with PVC coating.

    1 The syringe-tube together with 1 needle for injections and instructions for use are placed in a cardboard box.

    Storage conditions:

    At a temperature of 2-8 ° C in the dark place.

    Do not freeze.

    Keep out of the reach of children.

    Shelf life:

    3 years.

    Do not use after the expiration date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LS-002332
    Date of registration:13.08.2010
    The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland
    Manufacturer: & nbsp
    Representation: & nbspF.Hoffmann-La Roche Ltd. F.Hoffmann-La Roche Ltd. Switzerland
    Information update date: & nbsp12.09.2015
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