Peg-Alvograstim

Pegfilgrastim.

Each pre-filled syringe contains 6 mg of pegfilgrastim in 0.6 ml solution for injection.
Pegfilgrastim is produced in Escherichia coli cells by recombinant DNA technology followed by conjugation with polyethylene glycol (PEG).
The concentration is 10 mg/ml based on protein only and 20 mg/ml if the PEG moiety is included.
Excipients/Inactive Ingredients: Acetic acid, sodium hydroxide, sorbitol, polysorbate 20, water for injection.

Pharmacotherapeutic Group: Cytokines. ATC Code: L03AA13.
Pharmacology: Pharmacodynamics: Mechanism of Action and Pharmacodynamic effects: 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. Similarly 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: Distribution: After a single subcutaneous dose of pegfilgrastim, the peak serum concentration of pegfilgrastim occurs at 16 to 120 hours after dosing and serum concentrations of pegfilgrastim are maintained during the period of neutropenia after myelosuppressive chemotherapy.
Elimination: The elimination of pegfilgrastim is non-linear with respect to dose, serum clearance of pegfilgrastim decreases with increasing dose.
Pegfilgrastim appears to be mainly eliminated by neutrophil mediated clearance, 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 (see figure).
Due to neutrophil-mediated clearance mechanism, the pharmacokinetics of pegfilgrastim is not expected to be affected by renal or hepatic impairment. In an open-label, single dose study (n=31) various stages of renal impairment, including end-stage renal disease, had no impact on the pharmacokinetics of pegfilgrastim.
Limited data indicate that the pharmacokinetics of pegfilgrastim in elderly subjects (>65 years) is similar to that in adults.

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Toxicology: Preclinical Safety Data: Preclinical data from conventional studies of repeated dose toxicity revealed the expected pharmacological effects including increases in leukocyte count, myeloid hyperplasia in bone marrow, extramedullary haematopoiesis and splenic enlargement.
There were no adverse effects observed in offspring from pregnant rats given pegfilgrastim subcutaneously, but in rabbits pegfilgrastim has been shown to cause embryo/foetal toxicity (embryo-loss) at low subcutaneous doses. In rat studies, it was shown that pegfilgrastim may cross the placenta.
The relevance of these findings for humans is not known.

Peg-Alvograstim is indicated in adults for the reduction in the duration of neutropenia and the incidence of febrile neutropenia in patients treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes).

Posology: Peg-Alvograstim therapy should be initiated and supervised by physicians experienced in oncology and/or haematology.
One 6 mg dose (a single pre-filled syringe) of this medicine is recommended for each chemotherapy cycle, administered as a subcutaneous injection approximately 24 hours following cytotoxic chemotherapy.
Pediatric population: The experience in children is limited.
Currently available data are described in Adverse Reactions, and Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions, but no recommendation on a posology can be made.
Renal impairment: No dose change is recommended in patients with renal impairment, including those with end stage renal disease.

There is no experience with overdose of pegfilgrastim in humans.

Hypersensitivity to the active substance(s) or to any of the excipients listed in Excipients/Inactive Ingredients under Description.

Limited clinical data suggest a comparable effect on time to recovery of severe neutropenia for pegfilgrastim to filgrastim in patients with de novo acute myeloid leukaemia.
However, the long-term effects of pegfilgrastim have not been established in acute myeloid leukaemia; therefore, it should be used with caution in this patient population.
Granulocyte-colony stimulating factor can promote growth of myeloid cells in vitro and similar effects may be seen on some non-myeloid cells in vitro.
The safety and efficacy of pegfilgrastim have not been investigated in patients with myelodysplastic syndrome, chronic myelogenous leukaemia and in patients with secondary Acute Myeloid Leukaemia (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 acute myeloid leukaemia.
The safety and efficacy of pegfilgrastim administration in de novo AML patients aged <55 years with cytogenetics t(15;17) have not been established.
The safety and efficacy of pegfilgrastim have not been investigated in patients receiving high dose chemotherapy. Pegfilgrastim should not be used to increase the dose of cytotoxic chemotherapy beyond established dosage regimens.
Rare: (0.1/10.000 <1/1.000) pulmonary adverse effects, in particular interstitial pneumonia, have been reported after G-CSF administration. Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher risk (see Adverse Reactions).
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 Adult Respiratory Distress Syndrome (ARDS). In such circumstances pegfilgrastim should be discontinued at the discretion of the physician and the appropriate treatment given (see Adverse Reactions).
Common (≥1/100 to <1/10) but generally asymptomatic cases of splenomegaly and uncommon (=1/100 to <1/10) cases of splenic rupture, including some fatal cases, have been reported following administration of pegfilgrastim (see Adverse Reactions). Therefore, spleen size should be carefully monitored (e.g. clinical examination, ultrasound). A diagnosis of splenic rupture should be considered in patients reporting left upper abdominal pain or shoulder tip pain.
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. Special care should be taken when administering single or combination chemotherapeutic agents which are known to cause severe thrombocytopenia.
Sickle cell crises have been associated with the use of pegfilgrastim in patients with sickle cell disease (see Adverse Reactions). Therefore, physicians should exercise caution when administering pegfilgrastim in patients with sickle cell disease, should monitor appropriate clinical parameters and laboratory status and be attentive to the possible association of pegfilgrastim with splenic enlargement and vaso-occlusive crisis.
White blood cell (WBC) counts of 100 x 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 hrs after administration and is consistent with the pharmacodynamic effects of pegfilgrastim. Consistent with the clinical effects of pegfilgrastim and the potential for leukocytosis, a WBC count should be performed at regular intervals during therapy. If leukocyte counts exceed 50 x 10⁹/L after the expected nadir; pegfilgrastim should be discontinued immediately.
If a serious allergic reaction occurs, appropriate therapy should be administered, with close patient follow-up over several days. Pegfilgrastim should be permanently discontinued in patients who experience a serious allergic reaction (see Adverse Reactions).
The safety and efficacy of pegfilgrastim for the mobilisation of blood progenitor cells in patients or healthy donors has not been adequately evaluated.
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions.
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 results.
Peg-Alvograstim contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
Peg-Alvograstim contains less than 1 mmol (23 mg) sodium per 6 mg dose, i.e. essentially 'sodium-free'.
Effects on the ability to drive or use machines: No studies on the effects on the ability to drive and use machines have been performed with pegfilgrastim.

Pregnancy: There are no adequate data from the use of pegfilgrastim in pregnant women.
Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
The potential risk for humans is unknown.
Pegfilgrastim should not be used during pregnancy unless clearly necessary.
Breastfeeding: There is no clinical experience with breast-feeding women therefore, pegfilgrastim should not be administered to women who are breast-feeding.

Summary of the safety profile: Assessment of undesirable effects is based on the following frequency groupings: Very common: ≥1/10; common: ≥1/100, <1/10; uncommon: ≥1/1,000, <1/100; rare: ≥1/10,000, <1/1,000; very rare: <1/10,000; not known: cannot be estimated from the available data.
The most frequently reported adverse reactions were bone pain (very common ≥1/10) and musculoskeletal pain (very common ≥1/10). Bone pain was generally of mild to moderate severity, transient and could be controlled in most patients with standard analgesics.
Hypersensitivity-type reactions, including skin rash, urticaria, angioedema, dyspnoea, erythaema, flushing and hypotension occurred on initial or subsequent treatment with pegfilgrastim (uncommon ≥1/1000 to <1/100).
Serious allergic reactions, including anaphylaxis can occur in patients receiving pegfilgrastim (uncommon ≥1/1000 to <1/100) (see Precautions).
Splenomegaly, generally asymptomatic, is uncommon (≥1/1000 to <1/100) (see Precautions).
Splenic rupture including some fatal cases is uncommonly (≥1/1000 to <1/100) reported following administration of pegfilgrastim (see Precautions).
Uncommon (≥1/1000 to <1/100) pulmonary adverse effects including interstitial pneumonia, pulmonary oedema, pulmonary infiltrates and pulmonary fibrosis have been reported. Uncommonly (≥1/1000 to <1/100), cases have resulted in respiratory failure or Adult Respiratory Distress Syndrome (ARDS), which may be fatal (see Precautions).
Isolated cases of sickle cell crises have been reported in patients with sickle cell disease (uncommon ≥1/1000 to <1/100 in sickle cell patients) (see Precautions).
Tabulated summary of adverse reactions: The data listed as follows describe adverse reactions reported from clinical trials and spontaneous reporting.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See table.)

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Description of selected adverse reactions: Uncommon: (≥1/1000 to <1/100) cases of Sweet's syndrome have been reported, although in some cases underlying haematological malignancies may play a role.
Uncommon (≥1/1000 to <1/100) events of cutaneous vasculitis have been reported in patients treated with pegfilgrastim. The mechanism of vasculitis in patients receiving pegfilgrastim is unknown.
Injection site reactions, including injection site pain and injection site erythaema (common (≥1/100 to <1/10)) have occurred on initial or subsequent treatment with pegfilgrastim.
Uncommon (≥1/1000 to <1/100) cases of leukocytosis (White Blood Count (WBC) >100 x 10⁹/L) have been reported (see Precautions).
Reversible, mild to moderate elevations in uric acid and alkaline phosphatase, with no associated clinical effects, were uncommon (≥1/1000 to <1/100); reversible, mild to moderate elevations in lactate dehydrogenase, with no associated clinical effects, were uncommon (≥1/1000 to <1/100) in patients receiving pegfilgrastim following cytotoxic chemotherapy.
Nausea and headaches were very commonly observed in patients receiving chemotherapy.
Uncommon (≥1/1000 to <1/100) elevations in liver function tests (LFTs) for ALT (alanine aminotransferase) or AST (aspartate aminotransferase), have been observed in patients after receiving pegfilgrastim following cytotoxic chemotherapy. These elevations are transient and return to baseline.
Common (≥1/100 to <1/10) cases of thrombocytopenia have been reported.

Due to the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, pegfilgrastim should be administered approximately 24 hours after administration of cytotoxic chemotherapy. In clinical studies, 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 anti-metabolites has been shown to potentiate myelosuppression.
Possible interactions with other haematopoietic growth factors and cytokines have not been specifically investigated in clinical studies.
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 studies have not indicated an interaction of pegfilgrastim with any other medicinal products.

Special precautions for disposal and other handling: Before administration, Peg-Alvograstim solution should be inspected visually for particulate matter. Only a solution that is clear and colourless should be injected.
Excessive shaking may aggregate pegfilgrastim, rendering it biologically inactive.
Allow the pre-filled syringe to reach room temperature before injecting.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: The medicinal product must not be mixed with other medicinal products, particularly with sodium chloride solutions.

Store in a refrigerator (2°C-8°C).
Peg-Alvograstim may be exposed to room temperature (not above 30°C) for a maximum single period of up to 72 hours. Peg-Alvograstim 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 Peg-Alvograstim.
Shelf-Life: 2 years.

Haematopoietic Agents / Supportive Care Therapy

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

POM

Soln for inj (clear, colourless solution) (pre-filled syringe) 6 mg/0.6 mL x 1's, x 5's.