Lupifil-P

Lupifil-P (pegfilgrastim) is supplied in pre-filled syringes in the form of clear, colorless, preservative-free solution for subcutaneous use.
Each PFS of 0.6 mL contains Recombinant Pegylated Granulocyte Colony Stimulating Factor, r-DNA origin 6.0 mg, Acetate 0.35 mg, Sodium 0.021 mg, Sorbitol 30.0mg, Polysorbate 20 0.02 mg, Water for Injection q.s. to 0.6 ml.
Pegfilgastrim is a covalent conjugate of recombinant methionyl human G-CSF (filgrastim) and monomethoxypolyethylene glycol. It belongs to Hematopoietic growth factor therapeutic class. Filgrastim is a water-soluble 175 amino acid protein with a molecular weight of approximately 19 kilodaltons (KD). To produce pegfilgrastim, a 20 kD monomethoxypolyethylene glycol molecule is covalently bound to the N-terminal methionyl residue of filgrastim. The average molecular weight of pegfilgrastim is approximately 39 kD. Pegfilgrastim has reduced renal clearance and prolonged persistence in vivo as compared to filgrastim, which makes it behave like a sustained duration filgrastim.

Pharmacology: Mechanism of Action: Human granulocyte colony stimulating factor (GCSF) is a glycoprotein, which regulates the production and release of neutrophils from the bore marrow. It acts on hematopoietic cells by binding to specific cell surface receptors, thereby stimulating proliferation, differentiation, commitment, and end cell functional activation. Increase of white blood coil count (leucocytosis) is the predicted consequence of pegfilgrastim administration.
Pegfilgrastim and filgrastim have been shown to have identical mode of action, causing a marked increase in peripheral blood neutrophil counts within 24 hours, with minor increase in monocytes and/or lymphocytes.
Pharmacokinetics: The peak serum concentration of pegfilgrastim after a single subcutaneous dose of pegfilgrastim occurs at 16 to 120 hours and serum concentrations of pegfilgrastim are maintained during the period of neutropenia after myelosuppressive chemotherapy. The half-life of pegfilgrastim ranges from 15 to 80 hours after subcutaneous injection. 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. Elimination of pegfilgrastim is nonlinear with respect to dose, serum clearance of pegfilgrastim decreases with increases in dose. The pharmacokinetics of pegfilgrastim is not expected to be affected by renal or hepatic impairment. No gender related differences were observed in the pharmacokinetics of pegfilgrastim, and no differences were observed in the pharmacokinetics of geriatric patients (≥65 years of age) compared with younger patients (<65 years of age). The pharmacokinetics of pegflgrastim in pediatric patients indicates that the mean AUC appears to be similar to that for adult patients with the exception of the youngest age group (0-5 years).

For 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 leukemia and myelodysplastic syndromes).

The recommended dose of Lupifil-P (pegfilgrastim) is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Lupifil-P (pegfilgrastim) should not be administered between 14 days before and 24 hours after administration of cytotoxic chemotherapy.
Prior to administration visually inspect parenteral drug products for particulate matter and discoloration. Do not administer Lupifil-P (pegfilgrastim) if discoloration or particulates are observed.

The maximum amount of pegfilgrastim that can be safely administered in single or multiple doses has not been determined. Single subcutaneous dose of 300 mcg/kg has been administered to limited number of heathy volunteers and patients with non-small cell lung cancer without serious adverse effects. These patients experienced a mean maximum absolute neutrophil count (ANC) of 55 x 10⁹/L, with a corresponding mean maximum WBC of 67 x 10⁹/L. The absolute maximum ANC observed was 96 x 10⁹/L with a corresponding absolute maximum WBC observed of 120 x 10⁹/L. The duration of leukocytosis ranged from 6 to 13 days. The effectiveness of leukapheresis in the management of symptomatic individuals with pegfilgrastim-induced leukocytosis has not been studied.

Pegfilgrastim is contraindicated in patients with known hypersensitivity or history of serious allergic reactions to pegfilgrastim, filgrastim, E.coli derived proteins or to any other excipients in the product.

The safety and efficacy of pegfilgrastim has 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. Clinical data suggest that the effect on time of recovery of severe neutropenia between pegfilgrastim and filgrastim is comparable in patients with de novo acute myeloid leukemia. However, the long term effect of pegfilgrastim has not been established in acute myeloid leukemia (AML) therefore, it should be used with caution in this patient population. The safety and efficacy of pegfilgrastim has not been investigated in patients with myelocysplastic syndrome, chronic myelogenous leukaemia, and in patients with secondary Acute Myeloid Leukaemia (AML); therefore, it should not be used in such patients. 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. Lupifil-P (pegfilgrastim) contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine. 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 hours 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.
Splenic Rupture is seen in very rare cases, in some cases fatal, have been reported following the 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.
Acute Respiratory Distress Syndrome (ARDS) can occur in patients receiving pegfilgrastim. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving pegfilgrastim, for ARDS. Discontinue pegfilgrastim in patients with ARDS.
Serious Allergic Reactions including anaphylaxis, can occur in patients receiving pegfilgrastim. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue pegfilgrastim in patients with serious allergic reactions. Do not administer pegfilgrastim to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.
Severe Sickle Cell Crises can occur in patients with sickle cell disorders receiving pegfilgrastim. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim.
Potential for Tumor Growth Stimulatory Effects on Malignant Cells: The granulocyte-colony stimulating factor (G-CSF) receptor, through which pegfilgrastim and filgrastim act has been found on tumor cell lines. The possibility that pegfilgrastim can act as a growth factor for certain tumor type including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved cannot be excluded.
Renal Impairment: Pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary.
Use in Pregnancy & Lactation: See Use in Pregnancy & Lactation section for further information.
Use in Children: There are insufficient data to recommend the use of pegfilgrastim in children and adolescents under 18 years of age.
Use in the Elderly: No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

Pregnancy: 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 fetus is unknown. Pegfilgrastim should not be used during pregnancy unless clearly necessary.
Nursing Mothers: There is no clinical experience with lactating women; therefore pegfilgrastim should not be administered to women who are breast-feeding.

The most frequently reported adverse reactions with pegfilgrastim are bone pain (very common [≥1/:10]) and musculoskeletal pain (very common [≥1/10]). Bone pain is generally of mild to moderate severity, transient and can be controlled in most patients with standard analgesics.
Hypersensitivity-type reactions, including skin rash, urticaria, angioedema, dyspnoea, erythema, flushing, and hypotension can occur on initial or subsequent treatment with pegfilgrastim (uncommon [≥1/1,000 to <1/100]). Serious allergic reactions, including anaphylaxis can occur in patients receiving pegfilgrastim (uncommon [≥1/1,000 to <1/100]).
Splenomegaly, generally asymptomatic, is uncommon [≥1/1,000 to <1/100). Splenic rupture including some fatal cases is uncommonly [≥1/1,000 to <1/100) reported following administration of pegfilgrastim.
Following table summarizes the data of adverse reactions reported with pegfilgrastim. (See table.)

Click on icon to see table/diagram/image

No formal drug interaction studies between pegfilgrastim and other drugs have been performed. 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 studies. The potential for interaction with lithium 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 Innovator's 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. Due to the potential sensitivity of rapidly dividing myeloid cells in cytotoxic chemotherapy, pegfilgrastim should be administered approximately 24 hours after administration of cytotoxic chemotherapy. Increased hematopoietic activity of the bone marrow in response to growth factor therapy may result in transiently positive bone-imaging changes. Consider these findings when interpreting bone-imaging results.

Incompatibility: Pegfilgrastim is incompatible with sodium chloride solutions.

Storage & Instructions for Use: Lupifil-P (pegfilgrastim) should be stored in the refrigerator at 2° to 8°C (36°F to 46°F). 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. Avoid shaking. Prior to injection, Lupifil-P (pegfilgrastim) may be allowed to reach room temperature for a maximum of 72 hours. Any prefilled syringe left at room temperature for greater than 72 hours should be discarded.
Shelf Life: Shelf Life of the Lupifil-P 0.6 mL is 36 months from the date of manufacturing.

Haematopoietic Agents

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

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