Неуластим®

General characteristics. Structure:

Active ingredient: 6 mg of a pegfilgrastim in 1 unit-dose syringe of 0,6 ml.

Excipients: sodium acetate, sorbitol, polysorbate 20, water for injections.

Drug for the decrease in duration of a neutropenia, frequency of emergence of a febrile neutropenia and infections which are shown a febrile neutropenia at cytotoxic chemotherapy concerning malignant diseases.

Pharmacological properties:

Pharmacodynamics. Action mechanism. Hemopoietic growth factor. Pegfilgrastim - a covalent conjugate of a filgrastim (a recombinant human granulotsitarny colony stimulating factor [G-KSF]) with one molecule (PEG) 20 polyethyleneglycol of a kd, with the prolonged action as a result of decrease in renal clearance.

Similar to a filgrastim, pegfilgrasty regulates education and release of neutrophils from marrow, considerably increases quantity of neutrophils with the normal or increased functional activity (a chemotaxis and phagocytosis) in peripheral blood during 24 h and causes small increase in quantity of monocytes and/or lymphocytes.

As well as other hemopoietic growth factors, G-KSF can stimulate endothelial cells of in vitro.

Tranzitorny increase in leukocytes (leukocytosis) is the expected therapy effect pegfilgrastimy since corresponds to its pharmakodinamichesky effects. Any by-effects which are directly connected with such leukocytosis are not described.

Clinical performance. Single introduction of a pegfilgrastim after each cycle of myelosuppressive cytostatic therapy reduces duration of a neutropenia and frequency of emergence of a febrile neutropenia to similarly daily introduction of a filgrastim (on average, 11 daily introductions). It is also shown that use of a pegfilgrastim after chemotherapy considerably reduces the frequency of intravenous administration of antimicrobic drugs and hospitalization in connection with a febrile neutropenia.

Pharmacokinetics. Absorption. After single hypodermic introduction time of achievement of the maximum concentration (Tmax) of a pegfilgrastim of 16-120 h.

Distribution. Concentration of a pegfilgrastim in blood serum is maintained during the neutropenia period after myelosuppressive chemotherapy. Distribution of a pegfilgrastim is limited to plasma.

Removal. Removal of a pegfilgrastim nonlinear, dozozavisimy, saturable. The clearance is generally carried out by neutrophils (> 99%) and decreases with increase in a dose of a pegfilgrastim. According to the self-regulating mechanism of clearance, concentration of a pegfilgrastim in serum quickly decreases from the beginning of recovery of number of neutrophils.

Schedules of change of a median of concentration of a pegfilgrastim in blood serum and medians of the absolute number of neutrophils (ANN) in time after a single injection of 6 mg of a pegfilgrastim to the patients receiving chemotherapy.

Pharmacokinetics at special groups of patients. Considering clearance with participation of neutrophils probably that the pharmacokinetics of a pegfilgrastim does not change at a renal or liver failure.

Advanced age. The pharmacokinetics of a pegfilgrastim at patients is more senior than 65 years is similar to pharmacokinetics at adults.

Children. Average system exposure of AUC0-∞ made a pegfilgrastim after hypodermic introduction in a dose of 100 mkg/kg at children with sarcoma at the age of 6-11 years 22.0 ¼¬úþ/ml, at children of 12-21 years - 29.3 ¼¬úþ/ml, children have 0-5 years - 47.9 ¼¬úþ/ml. The terminal elimination half-life at children in the corresponding age groups made 20.2 h, 21.2 h and 30.1 h, respectively.

Indications to use:

For the decrease in duration of a neutropenia, frequency of emergence of a febrile neutropenia and infections which are shown a febrile neutropenia at cytotoxic chemotherapy concerning malignant diseases.

Route of administration and doses:

Adults (≥18 years): subcutaneously, 6 mg (one unit-dose syringe) in 24 h after carrying out each cycle of cytotoxic chemotherapy.

It is not necessary to apply Neulastim® less than in 14 days prior to, in time and less than in 24 h after introduction of cytotoxic chemotherapeutic means. It is necessary to cancel administration of the drug Neulastim® at increase in total quantity of leukocytes higher than 50 x 109/l.

Special groups of patients. Children: there are no recommendations about use of the drug Neulastim® for children and teenagers aged up to 18 years (not enough data).
To patients with body weight less than 45 kg the fixed dose (6 mg) of the drug Neulastim® should not be appointed (there are not enough data).

To the application instruction, address and destruction. The unit-dose syringe with the drug Neulastim® is intended only for disposable.

The drug Neulastim® represents sterile solution without preservatives. Before introduction solution of the drug Neulastim® should be examined on presence of strangers of visible particles. Administration only of transparent and colourless solution is allowed.

Excessive stirring can destroy pegfilgrasty, having made it biologically inactive.

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

Any unused drug or its remains should be destroyed according to health requirements.

Hit of medicines to the environment has to be minimized. It is not necessary to utilize drug by means of sewage or together with household waste. It is whenever possible necessary to use special systems for utilization of medicines.

Features of use:

Pregnancy. Researches at pregnant women were not conducted. At hypodermic introduction of a pegfilgrastim to pregnant rats of negative influence on posterity it is not revealed. At hypodermic introduction of low doses of a pegfilgrastim to rabbits signs of embrio-fetotoksichesky action (death of an embryo) were observed. Pegfilgrastim gets through a placenta of rats. The potential risk connected with influence on an embryo or a fruit of the person is unknown.

Breastfeeding period. Researches at the feeding women were not conducted therefore Neulastim® should not be applied during breastfeeding.

Treatment by the drug Neulastim® has to be carried out only under control of the oncologist or hematologist, having experience of use of G-KSF. Limited data demonstrate that efficiency of a pegfilgrastim and filgrastim is identical concerning time of stopping of a heavy neutropenia at patients with an acute myeloleukemia of de novo (see the section "Pharmacological Properties"). However it is necessary to show care at therapy by the drug Neulastim® at patients with an acute myeloleukemia of de novo as the long-term results of such therapy are not established.

G-KSF stimulates endothelial cells and can accelerate growth of myeloid cells, including malignant cells, and some not myeloid cells of in vitro.

Неуластим® it is not necessary to use at miyelodisplastichesky syndromes, a myelosis, a secondary acute myeloleukemia as safety and efficiency of drug at these groups of patients were not estimated. It is necessary to carry out especially carefully differential diagnosis between a blast transformation at a myelosis and an acute myeloleukemia.

Safety and efficiency of the drug Neulastim® at patients with an acute myeloleukemia of de novo are younger than 55 years with t translocation (15; 17) were not studied.

Safety and efficiency of the drug Neulastim® at the patients receiving high-dose chemotherapy were not studied.

Cough, fever and short wind in combination with radiological infiltrative changes, deterioration in function of lungs and increase in quantity of neutrophils can be signs respiratory a distress syndrome at adults. In that case at the discretion of the doctor of Neulastim® it is necessary to cancel and appoint the corresponding treatment.

Very exceptional cases of a rupture of a spleen after use of a pegfilgrastim, some - with a fatal outcome are registered. It is necessary to watch carefully the spleen sizes by means of tool inspection (ultrasonography). It is necessary to provide a possibility of a splenomegaly or a rupture of a spleen at patients with complaints to pain in an upper left part of a stomach and/or in an upper part of the left shoulder.

Monotherapy by the drug Neulastim® does not exclude development of thrombocytopenia and anemia at continuation of myelosuppressive chemotherapy in a full dose. It is recommended to define number of thrombocytes and a hematocrit regularly.

Неуластим® it is not necessary to use for increase in doses of cytotoxic chemotherapy above established in the dosing modes.

Development of drepanocytic crisis was associated with therapy pegfilgrastimy at patients with a sickemia. Therapy pegfilgrastimy at patients with a sickemia has to be carried out with care only after careful determination of potential risk and advantage.

The leukocytosis 100 x 109/l or more is observed less than at 1% of the patients receiving Neulastim® is temporary and is usually observed in 24-48 h after administration of drug according to its pharmakodinamichesky effects. Any by-effects which are directly connected with such leukocytosis are not described.

Safety and efficiency of a pegfilgrastim at mobilization of peripheral stem cells of blood at patients as appropriate were not estimated.

The increased hemopoietic activity of marrow in response to therapy by growth factors leads to tranzitorny positive changes at visualization of bones that it is necessary to take into account at interpretation of results.

In clinical trial at children among the undesirable phenomena most often, as well as at adults, the ostealgia was noted.

Influence on ability to driving of vehicles and work with cars and mechanisms. Researches on influence of the drug Neulastim® on ability to driving of vehicles and occupations were not conducted by potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

For assessment of frequency of side effects the following categories are used: very often (≥10%); often (≥1%, <10%); infrequently (≥0.1%, <1%); seldom (≥0.01%, <0.1%); very seldom (<0.01%, including separate cases).

Data of clinical trials. At the patients receiving Neulastim® after cytotoxic chemotherapy, the majority of the undesirable phenomena were caused by the basic malignant disease or cytotoxic chemotherapy.

Very often at use of drug it was reported about weak or moderate ostealgias which in most cases passed independently or were stopped by non-narcotic analgeziruyushchy means.

From skeletal and muscular system and connecting fabric: very often - an ostealgia; often - an arthralgia, a mialgiya, musculoskeletal pain, a dorsodynia, extremities and a neck.

The general frustration and disturbances in an injection site: often - pain and an erythema in the place of an injection, a stethalgia (not cardial), pain.

From a nervous system: often - a headache.

From blood and lymphatic system: infrequently - a leukocytosis.

From digestive tract: nausea (frequency is unknown).

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

Post-registration use of drug. From immune system: seldom - an anaphylaxis, rash, urticaria, a Quincke's disease, an asthma and arterial hypotension, an erythema and a hyperemia at the beginning of therapy or at the subsequent administration of drug. Sometimes resuming of treatment is followed by a recurrence of symptoms. In case of development of serious allergic reactions it is necessary to appoint the corresponding treatment with careful observation of the patient within several days. It is necessary to stop therapy pegfilgrastimy at development of serious allergic reactions.

From digestive tract: pains in an upper left part of a stomach (frequency is unknown).

From blood and lymphatic system: very seldom - a rupture of a spleen (in certain cases with a fatal outcome), a splenomegaly (frequency is unknown), vazookklyuzionny crisis (frequency is unknown).

From respiratory system, bodies of a thorax and a mediastinum: cough (frequency is unknown), an asthma (frequency is unknown), infiltrates in lungs (frequency is unknown), breath dysfunction (frequency is unknown), a respiratory distress syndrome (frequency is unknown).

The general frustration and disturbances in an injection site: fever (frequency is unknown).

From skin and a hypodermic fatty tissue: seldom - a syndrome It is twisted (an acute febrile dermatosis); a skin vasculitis (settlement frequency of messages is 0.00038%).

Interaction with other medicines:

Cytotoxic chemotherapy. Because of possible sensitivity of quickly sharing myeloid cells to cytotoxic therapy of Neulastim® it is necessary to enter in 24 h after introduction of cytotoxic chemotherapeutic means. In clinical trials drug was safely used in 14 days prior to introduction of cytotoxic chemotherapeutic means.

Ftoruratsil or other antimetabolites. Strengthening of oppression of a hemopoiesis of in vivo (at animals). Interaction with other hemopoietic growth factors and cytokines is unknown.

The possibility of interaction with lithium which also promotes release of neutrophils was specially not investigated. There is no confirmation that this interaction can be dangerous.

The researches devoted to specific interactions or metabolism did not carry out.

Safety and efficiency of the drug Neulastim® at the patients receiving the chemotherapy leading to the delayed miyelosupressiya (for example, drugs from group of derivatives of a nitrozomochevina), was not studied.

Signs of interaction of the drug Neulastim® with other medicines on the present are not recorded.

Incompatibility. Неуластим® it is incompatible with chloride sodium solutions.

Contraindications:

Hypersensitivity to the proteins received with E.coli use, to a filgrastim, a pegfilgrastim or to any other component of drug.

Neutropenia at a myelosis and miyelodisplastichesky syndromes.

Acute leukosis.

For increase in doses of cytotoxic chemotherapy is higher established in the dosing modes. Co-administration with a cytotoxic himio-and radiation therapy.

Pregnancy and period of breastfeeding.

Age up to 18 years.

With care. Malignant and pretumor diseases of myeloid character (including acute myeloleukemia of de novo and secondary).

In a combination with high-dose chemotherapy.

Sickemia.

Hereditary intolerance of fructose (the structure contains sorbitol).

Overdose:

At single hypodermic administration of drug in a dose of 300 mkg/kg of the serious undesirable phenomena did not arise neither at healthy volunteers, nor at patients with not small-celled cancer of a lung. By-effects at overdose did not differ from by-effects at use of drug in the recommended doses.

Storage conditions:

Period of validity 3 years. Not to use after the period of validity specified on packaging.

At a temperature of 2-8 °C in the place protected from light. Not to freeze. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Solution for hypodermic introduction of 6 mg / 0.6 ml

On 6 mg / 0.6 drug ml in an unit-dose syringe which case is manufactured of glass (a hydrolytic class 1 on EF), the piston - from plastic, with a stopper from the butyl rubber laminated by a ftorpolimer. On the other hand the unit-dose syringe is corked by a tip from the butyl rubber laminated by a ftorpolimer. 1 unit-dose syringe together with 1 sterile injection cannula (the injection cannula is enclosed in hermetically corked plastic container) and the application instruction is placed in a cardboard pack.