Neulastim (Solution) Instructions for Use

Marketing Authorization Holder

Amgen Europe, B.V. (Netherlands)

Manufactured By

Amgen Manufacturing, Limited (Puerto Rico)

Packaging and Quality Control Release

AMGEN EUROPE, B.V. (Netherlands)

Or

DOBROLEK, LLC (Russia)

ATC Code

L03AA13 (Pegfilgrastim)

Active Substance

Pegfilgrastim (Rec.INN registered by WHO)

Dosage Form

Neulastim

Solution for subcutaneous administration 6 mg/0.6 ml: syringe 0.6 ml 1 pc. in a kit with an injection needle

Dosage Form, Packaging, and Composition

Solution for subcutaneous administration transparent, colorless, free from mechanical inclusions.

Excipients: acetic acid – 0.35 mg, sodium hydroxide – q.s., sorbitol – 30 mg, polysorbate 20 – 0.02 mg, water for injection – up to 0.6 ml.

0.6 ml – glass syringes with a capacity of 1 ml (1) with a built-in injection needle (1 pc.) – cardboard packs^× with a fixator.
0.6 ml – glass syringes with a capacity of 1 ml (1) with a built-in injection needle (1 pc.) – contour cell packs (1) – cardboard packs^×.

^× each pack is affixed with transparent protective labels for first opening control, having a longitudinal colored stripe.

Clinical-Pharmacological Group

Leukopoiesis stimulant

Pharmacotherapeutic Group

Leukopoiesis stimulator

Pharmacological Action

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

Similar to filgrastim, Pegfilgrastim regulates the formation and release of neutrophils from the bone marrow, significantly increases the number of neutrophils with normal or increased functional activity (chemotaxis and phagocytosis) in the peripheral blood within 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, as it corresponds to its pharmacodynamic effects. No adverse events directly related to such leukocytosis have been described.

Clinical efficacy

A single administration of pegfilgrastim after each cycle of myelosuppressive cytotoxic therapy reduces the duration of neutropenia and the incidence of febrile neutropenia similar to daily administration of filgrastim (on average, 11 daily administrations). It has also been shown that the use of pegfilgrastim after chemotherapy significantly reduces the frequency of intravenous administration of antimicrobial drugs and hospitalization due to febrile neutropenia.

Pharmacokinetics

Absorption

After a single subcutaneous administration, the T_max of pegfilgrastim is 16-120 hours.

Distribution

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

The distribution of pegfilgrastim is limited to plasma.

Elimination

The elimination of pegfilgrastim is nonlinear, dose-dependent, and saturable. Clearance is primarily carried out by neutrophils (>99%) and decreases with increasing dose of pegfilgrastim. In accordance with the self-regulating clearance mechanism, the serum concentration of pegfilgrastim rapidly decreases with the onset of neutrophil count recovery.

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

Pharmacokinetics in special patient groups

Given the neutrophil-mediated clearance, 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 exposure AUC_0-∞ of pegfilgrastim after subcutaneous administration at a dose of 100 mcg/kg in children with sarcoma aged 6-11 years was 22.0 mcg×h/ml, in children 12-21 years – 29.3 mcg×h/ml, in children 0-5 years – 47.9 mcg×h/ml. The terminal T_1/2 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, during cytotoxic chemotherapy for malignant diseases.

ICD codes

Dosage Regimen

Adults (≥18 years) the drug is administered subcutaneously at a dose of 6 mg (1 syringe-tube) 24 hours after each cycle of cytotoxic chemotherapy.

Neulastim^® should not be used less than 14 days before, during, and less than 24 hours after the administration of cytotoxic chemotherapeutic agents.

Administration of Neulastim^® should be discontinued if the total leukocyte count increases above 50 × 10⁹/L.

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

Patients with a body weight less than 45 kg should not be prescribed a fixed dose (6 mg) of Neulastim^® (insufficient data).

Instructions for use, handling and disposal

The syringe-tube with Neulastim^® is intended for single use only.

Neulastim^® is a sterile, preservative-free solution.

Before administration, the Neulastim^® solution should be inspected for the presence of foreign visible particles. Only a clear and colorless solution should be administered.

Excessive shaking may destroy Pegfilgrastim, making it biologically inactive.

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

Any unused drug or its residues should be disposed of in accordance with sanitary requirements.

Environmental release of medicinal products should be minimized. The drug should not be disposed of via wastewater or with household waste. If possible, special systems for the disposal of medicinal products should be used.

Adverse Reactions

The following categories are used to assess the frequency of adverse effects: very common (≥10%); common (≥1%, <10%); uncommon (≥0.1%, <1%); rare (≥0.01%, <0.1%); very rare (<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 or moderate bone pain was very commonly reported with the use of the drug, which in most cases resolved on its own or was relieved by non-narcotic analgesics.

Musculoskeletal and connective tissue disorders very common – bone pain; common – arthralgia, myalgia, musculoskeletal pain, back pain, limb and neck pain.

General disorders and administration site conditions common – pain and erythema at the injection site, chest pain (non-cardiac), pain.

Nervous system disorders common – headache.

Blood and lymphatic system disorders: uncommon – leukocytosis.

Gastrointestinal disorders nausea (frequency unknown).

Investigations very common – reversible, mild or moderate clinically insignificant increase in alkaline phosphatase and LDH activity; common – reversible, mild or moderate clinically insignificant increase in uric acid.

Post-marketing use of the drug

Immune system disorders rare – anaphylaxis, rash, urticaria, angioedema, dyspnea and arterial hypotension, erythema and hyperemia at the start of therapy or upon subsequent administration of the drug. Sometimes resumption of treatment is accompanied by a recurrence of symptoms. In case of development of serious allergic reactions, appropriate treatment should be prescribed with careful monitoring of the patient for several days. Pegfilgrastim therapy 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 – splenic rupture (in some cases fatal), splenomegaly (frequency unknown), vaso-occlusive crisis (frequency unknown).

Respiratory, thoracic and mediastinal disorders: cough (frequency unknown), dyspnea (frequency unknown), pulmonary infiltrates (frequency unknown), impaired respiratory function (frequency unknown), respiratory distress syndrome (frequency unknown).

General disorders and administration site conditions fever (frequency unknown).

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

Contraindications

• Neutropenia in chronic myeloid leukemia and myelodysplastic syndromes;
• Acute leukemia;
• To increase the doses of cytotoxic chemotherapy above those established in the dosing regimens;
• Concomitant administration with cytotoxic chemo- and radiation therapy;
• Pregnancy;
• Breastfeeding period;
• Age under 18 years;
• Hypersensitivity to proteins derived from E. coli, filgrastim, pegfilgrastim or any other component of the drug.

With caution the drug should be prescribed for malignant and pre-tumor diseases of myeloid nature (including acute myeloid leukemia de novo and secondary); in combination with high-dose chemotherapy; with sickle cell anemia, with hereditary fructose intolerance (contains sorbitol).

Use in Pregnancy and Lactation

Studies in pregnant women have not been conducted.

No negative effects on offspring were detected with subcutaneous administration of pegfilgrastim to pregnant rats. With subcutaneous administration of low doses of pegfilgrastim to rabbits, signs of embryo-fetotoxic action (embryo death) were observed. Pegfilgrastim crosses the placenta in rats. The potential risk associated with effects on the human embryo or fetus is unknown.

Studies in lactating women have not been conducted, therefore Neulastim^® should not be used during breastfeeding.

Pediatric Use

Contraindicated: age under 18 years.

Special Precautions

Treatment with Neulastim^® should be carried out only under the supervision of an oncologist or hematologist with experience in the use of G-CSF.

Limited data indicate that the efficacy of pegfilgrastim and filgrastim is the same in terms of time to resolution of severe neutropenia in patients with acute myeloid leukemia de novo. However, caution should be exercised when treating with Neulastim^® in patients with acute myeloid leukemia de novo, as the long-term outcomes of such therapy have not been established.

G-CSF stimulates endothelial cells and may accelerate the growth of myeloid cells, including malignant cells, and some non-myeloid cells in vitro. Neulastim^® should not be used for myelodysplastic syndromes, chronic myeloid leukemia, secondary acute myeloid leukemia, as the safety and efficacy of the drug in these patient groups have not been evaluated. Differential diagnosis between blast transformation in chronic myeloid leukemia and acute myeloid leukemia should be carried out with particular care.

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

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

Cough, fever and dyspnea in combination with radiological infiltrative changes, deterioration of lung function and an increase in the number of neutrophils may be signs of respiratory distress syndrome in adults. In such a case, Neulastim^® should be discontinued at the physician’s discretion and appropriate treatment should be prescribed.

Very rare cases of splenic rupture have been reported following the use of pegfilgrastim, some with fatal outcome. The size of the spleen should be carefully monitored by instrumental examination (ultrasound examination). The possibility of splenomegaly or splenic rupture should be considered in patients complaining of pain in the upper left abdomen and/or in the upper part of the left shoulder.

Monotherapy with Neulastim^® does not preclude the development of thrombocytopenia and anemia with continued myelosuppressive chemotherapy at full dose. Platelet count and hematocrit should be regularly determined.

Neulastim^® should not be used to increase the doses of cytotoxic chemotherapy 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. Pegfilgrastim therapy in patients with sickle cell anemia should be used with caution only after careful determination of the potential risks and benefits.

Leukocytosis of 100 × 10⁹/L or more is observed in less than 1% of patients receiving Neulastim^®, is transient and is usually observed 24-48 hours after drug administration in accordance with its pharmacodynamic effects. No adverse events directly related to such leukocytosis have been described.

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

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

In a clinical trial in children, among adverse events, bone pain was most frequently reported, as in adults.

Effect on ability to drive vehicles and operate machinery

Studies on the effect of Neulastim^® on the ability to drive vehicles and engage in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions have not been conducted.

Overdose

With a single subcutaneous administration of the drug at a dose of 300 mcg/kg, no serious adverse events occurred in either healthy volunteers or patients with non-small cell lung cancer. Adverse events with overdose did not differ from adverse events with normal use of the drug at recommended doses.

Drug Interactions

Cytotoxic chemotherapy: due to the possible sensitivity of rapidly dividing myeloid cells to cytotoxic therapy, Neulastim^® should be administered 24 hours after the administration of cytotoxic chemotherapeutic agents. In clinical studies, the drug was safely used 14 days before the administration 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 the release of neutrophils, has not been specifically studied. There is no confirmation that this interaction could be dangerous.

Studies on specific interactions or metabolism have not been conducted.

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

No signs of interaction of Neulastim^® with other drugs have been recorded to date.

Incompatibility

Neulastim^® is incompatible with sodium chloride solutions.

Storage Conditions

The drug should be stored out of the reach of children, protected from light at a temperature from 2°C (35.6°F) to 8°C (46.4°F); do not freeze.

Shelf Life

Shelf life – 3 years. The drug should not be used after the expiration date printed on the packaging.

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.