Lutholaz

Each pre-filled syringe contains Pegfilgrastim 6 mg/0.6 mL.
Excipients/Inactive Ingredients: Acetic acid, Sodium acetate, Sorbitol, Polysorbate 20 and Water for injection.

Pharmacotherapeutic group: Immunostimulants, colony stimulating factor. ATC Code: L03AA13.
Pharmacology: Pharmacodynamics: Human granulocyte colony stimulating factor (G-CSF) is a glycoprotein, which regulates the production and release of neutrophils from the bone marrow. Pegfilgrastim is a covalent conjugate of recombinant human G-CSF (r-metHuG-CSF) with a single 20 kd polyethylene glycol (PEG) molecule. Pegfilgrastim is a sustained duration form of filgrastim due to decreased renal clearance.
Pegfilgrastim and filgrastim have been shown to have identical modes of action, causing a marked increase in peripheral blood neutrophil counts within 24 hours, with minor increases in monocytes and/or lymphocytes. Similarity to filgrastim, neutrophils produced in response to pegfilgrastim show normal or enhanced function as demonstrated by tests of chemotactic and phagocytic function. As with other haematopoietic growth factors, G-CSF has shown in vitro stimulating properties on human endothelial cells. G-CSF can promote growth of myeloid cells, including malignant cells, in vitro and similar effects may be seen on some non-myeloid cells in vitro.
Pharmacokinetics: Absorption: After a single subcutaneous dose of pegfilgrastim, the peak serum concentration of pegfilgrastim occurs at 16 to 120 hours after dosing.
Distribution: Serum concentrations of pegfilgrastim are maintained during the period of neutropenia after myelosuppressive chemotherapy.
Elimination: The elimination of pegfilgrastim is non-linear with respects to dose; serum clearance of pegfilgrastim decreases with increasing dose. Pegfilgrastim appears to be mainly eliminated by neutrophil mediated clearance (>99%), which becomes saturated at higher doses. Consistent with a self-regulating clearance mechanism, the serum concentration of pegfilgrastim declines rapidly at the onset of neutrophil recovery.
Pharmacokinetics in special populations: Due to the neutrophil-mediated clearance mechanism, the pharmacokinetics of pegfilgrastim is not expected to be affected by renal or hepatic impairment.
Limited data indicate that the pharmacokinetics of pegfilgrastim in elderly subjects (>65 years) is similar to that in adults.
The pharmacokinetics of pegfilgrastim were studied in 37 paediatric patients with sarcoma, who received 100 μg/kg pegfilgrastim after the completion of VAdriaC/IE chemotherapy. The youngest age group (0-5 years) had a higher mean exposure to pegfilgrastim (AUC) (± Standard Deviation) (47.9 ± 22.5 μg·hr/ml) than older children aged 6-11 years and 12-21 years (22.0 ± 13.1 μg·hr/ml and 29.3 ± 23.2 μg·hr/ml, respectively). With the exception of the youngest age group (0-5 years), the mean AUC in paediatric subjects appeared similar to that for adult patients with high-risk stage II-IV breast cancer and receiving 100 μg/kg pegfilgrastim after the completion of doxorubicin/docetaxel.

Reduction in the duration of neutropenia, the incidence of febrile neutropenia and the incidence of infection as manifested by febrile neutropenia in patients treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes).

Recommended Dose: Pegfilgrastim therapy should be initiated and supervised by physicians experienced in oncology and/or haematology.
Adults: One 6 mg dose (a single pre-filled syringe) of pegfilgrastim is recommended for each chemotherapy cycle, given at least 24 hours after cytotoxic chemotherapy.
Special populations: Paediatric use: The safety and efficiency of pegfilgrastim in children and adolescents under 18 years of age have not been established.
Renal impairment: No dosage adjustment is required for patients with in renal impairment.
Hepatic impairment: No dosage adjustment is required for patients with in hepatic impairment.
Mode of Administration: Pegfilgrastim is injected subcutaneously via the thigh, abdomen or upper arm.

Overdose and Treatment: Single doses of 300 μg/kg have been administered subcutaneously to a limited number of healthy volunteers and patients with non-small cell lung cancer without serious adverse reactions. The adverse events were similar to those in subjects receiving lower doses of pegfilgrastim.

Hypersensitivity to the pegfilgrastim (active ingredient), filgrastim, any ingredient in the formulation, or proteins derived from Escherichia coli.

Traceability: In order to improve the traceability of granulocyte-colony stimulating factors (G-CSFs), the trade name of the administered product should be clearly recorded in the patient file.
Limited clinical data suggest that the effect on time to recovery of severe neutropenia between pegfilgrastim and filgrastim is comparable in patients with de novo acute myeloid leukaemia (AML). However, the long-term effects of pegfilgrastim have not been established in AML; therefore, it should be used with caution in this patient population.
Granulocyte-colony stimulating factor (G-CSF) can promote growth of myeloid cells in vitro and similar effects may be seen on some non-myeloid cells in vitro.
No dose change is recommended in patients with renal impairment, including those with end-stage renal disease.
The safety and efficacy of pegfilgrastim have not been investigated in patients with myelodysplastic syndrome, chronic myelogenous leukaemia, and in patients with secondary AML; therefore, it should not be used in such patients. Particular care should be taken to distinguish the diagnosis of blast transformation of chronic myeloid leukaemia from AML.
The safety and efficacy of pegfilgrastim administration in de novo AML patients aged < 55 years with cytogenetics t(15;17) have not been established.
This medicinal product should not be used to increase the dose of cytotoxic chemotherapy beyond established dosage regimens.
Pulmonary adverse events: The onset of pulmonary signs such as cough, fever, and dyspnoea in association with radiological signs of pulmonary infiltrates, and deterioration in pulmonary function along with increased neutrophil count may be preliminary signs of Adults Respiratory Distress Syndrome (ARDS). In such circumstances pegfilgrastim should be discontinued at the discretion of the physician and the appropriate treatment given.
Glomerulonephritis: Glomerulonephritis has been reported in patients receiving filgrastim and pegfilgrastim. Generally, events of glomerulonephritis resolved after dose reduction or withdrawal of filgrastim and pegfilgrastim. Urinalysis monitoring is recommended.
Capillary leak syndrome: Capillary leak syndrome has been reported after granulocyte-colony stimulating factor administration and is characterized by hypotension, hypoalbuminaemia, oedema and hemoconcentration. Patients who develops symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care.
Splenomegaly and splenic rupture: Uncommon but generally asymptomatic cases of splenomegaly and uncommon cases of splenic rupture, including some fatal cases, have been reported following administration of pegfilgrastim. Spleen size should be carefully monitored. Patients receiving pegfilgrastim who report left upper abdominal and/or shoulder tip pain should be evaluated for an enlarged spleen or splenic rupture.
Thrombocytopenia and anaemia: Treatment with pegfilgrastim alone does not preclude thrombocytopenia and anaemia because full dose myelosuppressive chemotherapy is maintained on the prescribed schedule. Regular monitoring of platelet count and haematocrit is recommended.
Medication error as a result of device failure: There is a risk of medication error, particularly a partial or missed dose of pegfilgrastim, in the event of a device failure. In the event of a partial or missed dose, patients may be at increased risk of events such as neutropenia, febrile neutropenia and/or infection than if the dose had been correctly delivered. Comprehensive instructions for use for healthcare professionals and patients are given in the package leaflet. The patient should also be given the Patient Alert Card.
Sickle cell anemia: Sickle cell crisis has been associated with the use of pegfilgrastim in patients with sickle cell trait or sickle cell disease. Physicians should use caution when prescribing the use of pegfilgrastim in patients with sickle cell trait or sickle cell disease.
Leukocytosis: White blood cell (WBC) counts of 100 × 10⁹/L or greater have been observed in less than 1% of patients receiving pegfilgrastim. No adverse events directly attributable to this degree of leukocytosis have been reported. Such elevation in white blood cells is transient, typically seen 24 to 48 hours after administration and is consistent with the pharmacodynamic effects of this medicine. Consistent with the clinical effects and the potential for leukocytosis, a WBC count should be performed at regular intervals during therapy. If leukocyte counts exceed 50 × 10⁹/L after the expected nadir, this medicine should be discontinued immediately.
Hypersensitivity: Hypersensitivity, including anaphylactic reactions, occurring on initial or subsequent treatment have been reported in patients treated with pegfilgrastim. Permanently discontinue pegfilgrastim in patients with clinically significant hypersensitivity. Do not administer pegfilgrastim to patients with a history of hypersensitivity to pegfilgrastim or filgrastim. If a serious allergic reaction occurs, appropriate therapy should be administered, with close patient follow-up over several days.
Stevens-Johnson syndrome: Stevens-Johnson syndrome (SJS), which can be life-threatening or fatal, has been reported rarely in association with pegfilgrastim treatment. If the patient has developed SJS with the use of pegfilgrastim, treatment with pegfilgrastim must not be restarted in this patient at any time.
Immunogenicity: As with all therapeutic proteins, there is a potential for immunogenicity. Rates of generation of antibodies against pegfilgrastim is generally low. Binding antibodies do occur as expected with all biologics; however, they have not been associated with neutralizing activity at present.
Aortitis: Aortitis has been reported after G-CSF administration in healthy subjects and in cancer patients. The symptoms experienced included fever, abdominal pain, malaise, back pain and increased inflammatory markers (e.g. c-reactive protein and white blood cell count). In most cases aortitis was diagnosed by CT scan and generally resolved after withdrawal of G-CSF.
Other warning: The safety and efficacy of pegfilgrastim for the mobilization of blood progenitor cells in patients or healthy donors has not been adequately evaluated.
Increased haematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone-imaging findings. This should be considered when interpreting bone-imaging result.
Pegfilgrastim contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
This medicine contains less than 1 mmol (23 mg) sodium per 6 mg dose, that is to say essentially 'sodium-free'.
Effects on ability to drive and use machine: No studies on the effects on the ability to drive and use machines have been performed.

Pregnancy: Category C.
There are no data from the use of pegfilgrastim in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk to the human embryo or foetus is unknown. Pegfilgrastim should not be used during pregnancy unless clearly necessary.
Lactation: Not known whether pegfilgrastim is distributed into milk, therefore pegfilgrastim should not be administered in lactating women.

Very common: Nervous system disorders: Headache.
Gastrointestinal disorders: Nausea.
Musculoskeletal and connective tissue disorders: Bone pain.
Common: Blood and lymphatic system disorders: Thrombocytopenia, leukocytosis.
Skin and subcutaneous tissue disorders: Contact dermatitis.
Musculoskeletal and connective tissue disorders: Musculoskeletal pain (myalgia, arthralgia, pain in extremity, back pain, musculoskeletal pain, neck pain).
General disorders and administrative site conditions: Injection site pain, application site reaction, non-cardiac chest pain.
Uncommon: Blood and lymphatic system disorders: Sickle cell crisis, splenomegaly, splenic rupture.
Immune system disorders: Hypersensitivity reactions, anaphylaxis.
Metabolism and nutrition disorders: Elevations in uric acid.
Vascular disorders: Capillary leak syndrome.
Respiratory, thoracic and mediastinal disorders: Acute respiratory distress syndrome (ARDS), pulmonary adverse reaction (interstitial pneumonia, pulmonary oedema, pulmonary infiltrates and pulmonary fibrosis), haemoptysis.
Skin and subcutaneous tissue disorders: Sweet's syndrome (acute febrile dermatosis), cutaneous vasculitis.
Renal and urinary disorders: Glomerulonephritis.
General disorders and administrative site conditions: Injection site reaction.
Rare: Vascular disorders: Aortitis.
Respiratory, thoracic and mediastinal disorders: Pulmonary haemorrhage.
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome.

Due to the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, pegfilgrastim should be administered at least 24 hours after administration of cytotoxic chemotherapy. In clinical trials, pegfilgrastim has been safely administered 14 days before chemotherapy. Concomitant use of pegfilgrastim with any chemotherapy agent has not been evaluated in patients. In animal models concomitant administration of pegfilgrastim and 5-fluorouracil (5-FU) or other antimetabolites has been shown to potentiate myelosuppression.
Possible interactions with other haematopoietic growth factors and cytokines have not been specifically investigated in clinical trials.
The potential for interaction with lithium, which also promotes the release of neutrophils, has not been specifically investigated. There is no evidence that such an interaction would be harmful.
The safety and efficacy of pegfilgrastim have not been evaluated in patients receiving chemotherapy associated with delayed myelosuppression e.g. nitrosoureas.
Specific interaction or metabolism studies have not been performed; however, clinical trials have not indicated an interaction of pegfilgrastim with any other medicinal products.

Store in a refrigerator (2-8°C).
Pegfilgrastim may be exposed to room temperature (not above 30°C) for a maximum single period of up to 72 hours.
Pegfilgrastim left at room temperature for more than 72 hours should be discarded.
Do not freeze. Accidental exposure to freezing temperatures for a single period of less than 24 hours does not adversely affect the stability of pegfilgrastim.
Keep the container in the outer carton in order to protect from light.

Supportive Care Therapy / Haematopoietic Agents

L03AA13 - pegfilgrastim ; Belongs to the class of colony stimulating factors. Used as immunostimulants.

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