Pefloxacin mesylate

333.36

429.137

274-613-9

5IAD0UV3FH

758944

DTXSID8045935

2933599090

127

2.19820

1.32 g/cm3

60

529.1ºC at 760 mmHg

273.8ºC

Water-soluble

Store refrigerated between 2 deg to 8 °C (36 deg to 46 °F) in the carton to protect from light. Do not shake. Discard syringes stored at room temperature for more than 48 hours. Avoid freezing; if frozen, thaw in the refrigerator before administration.

187 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]|176.1 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

11-34

16-26-36/37/39-45

F,C

P201, P202, P261, P264, P270, P271, P280, P281, P301+P310, P301+P312, P302+P352, P304+P340, P305+P351+P338, P308+P313, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, P501

H301

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

|Danger|H301 (25%): Toxic if swallowed [Danger Acute toxicity, oral]|P201, P202, P261, P264, P270, P271, P280, P281, P301+P310, P301+P312, P302+P352, P304+P340, P305+P351+P338, P308+P313, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 4 companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Filgrastim and sargramostim have not been linked to instances of significant serum enzyme elevations during therapy and have not been implicated in cases of clinically apparent liver injury. In multiple large prelicensure studies, acute liver injury was not mentioned as an adverse event and serum aminotransferase elevations were elevated in a similar or lower proportion of patients receiving these growth factors than in placebo or comparator arms. G-CSF and GM-CSF are often given to critically ill patients receiving high doses of chemotherapy in whom serum enzyme elevations are common, but which usually can be attributed to the chemotherapy itself or the underlying malignancy. In addition, serum alkaline phosphatase elevations during filgrastim and sargramostim therapy may be from a bone source rather than the liver, in that both agents stimulate the bone marrow and not infrequently cause bone pain. In children, colony stimulating factors can cause hepatomegaly due to extramedullary hematopoiesis. However, since licensure and wide scale use, there have been no published reports of idiosyncratic acute liver injury attributed to filgrastim, pegfilgrastim or sargramostim.

Potential pharmacologic interaction /with lithium/ (potentiation of neutrophil release); more frequent monitoring of neutrophil counts is recommended.|Concomitant use of pegfilgrastim and fluorouracil or other antimetabolites has not been evaluated in patients. In animal studies, increased mortality has been reported in mice administered pegfilgrastim at 0, 1, and 3 days prior to fluorouracil administration; administration of pegfilgrastim 24 hours following fluorouracil administration did not adversely affect survival.

Although not reported to date in patients receiving pegfilgrastim, severe sickle cell crisis (which has been fatal in at least one case) has been reported in patients with sickle cell disease (specifically, homozygous sickle cell anemia, sickle cell-hemoglobin C disease, and sickle cell-beta+-thalassemia disease) who received filgrastim for PBPC mobilization or following chemotherapy. Pegfilgrastim should be used with caution in patients with sickle cell disease, and only after careful consideration of the potential risks and benefits. Patients with sickle cell disease who receive pegfilgrastim should be well hydrated and monitored for the occurrence of sickle cell crisis. If severe sickle cell crisis occurs, supportive care should be initiated, and interventions to ameliorate the underlying event (e.g., therapeutic red blood cell exchange transfusion) should be considered.

While data specific to pegfilgrastin were not located(SRC, 2013), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are, therefore, discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

Granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) are glycosylated polypeptides that induce an increase in the proliferation and maturation of white blood cells including neutrophils and monocytes-macrophages. Recombinant forms of these colony stimulating factors are used to treat severe neutropenia in patients receiving cancer chemotherapy or undergoing hematopoietic cell transplantation. Recombinant forms include filgrastim (G-CSF) and sargramostim (GM-CSF), both of which are commercially available for therapy of severe neutropenia and bone marrow failure. Neither filgrastim nor sargramostim have been linked to serum enzyme elevations during therapy or to clinically apparent liver injury.

Hematologic Growth Factors

Pegfilgrastim is used to decrease the risk of infectious complications (as manifested by febrile neutropenia) in patients with nonmyeloid malignancies receiving myelosuppressive antineoplastic therapy that is associated with a clinically important risk of severe neutropenia with fever. /Included in US product label/|Myelosuppressive chemotherapy can lead to dose-limiting febrile neutropenia. Prophylactic use of recombinant human G-CSF such as daily filgrastim and once-per-cycle pegfilgrastim may reduce the incidence of febrile neutropenia. This comparative study examined the effect of pegfilgrastim versus daily filgrastim on the risk of hospitalization. This retrospective United States claims analysis utilized 2004-2009 data for filgrastim- and pegfilgrastim-treated patients receiving chemotherapy for non-Hodgkin's lymphoma (NHL) or breast, lung, ovarian, or colorectal cancers. Cycles in which pegfilgrastim or filgrastim was administered within 5 days from initiation of chemotherapy (considered to represent prophylaxis) were pooled for analysis. Neutropenia-related hospitalization and other healthcare encounters were defined with a "narrow" criterion for claims with an ICD-9 code for neutropenia and with a "broad" criterion for claims with an ICD-9 code for neutropenia, fever, or infection. Odds ratios (OR) for hospitalization and 95% confidence intervals (CI) were estimated by generalized estimating equation (GEE) models and adjusted for patient, tumor, and treatment characteristics. Per-cycle healthcare utilization and costs were examined for cycles with pegfilgrastim or filgrastim prophylaxis. /The authors/ identified 3,535 patients receiving G-CSF prophylaxis, representing 12,056 chemotherapy cycles (11,683 pegfilgrastim, 373 filgrastim). The mean duration of filgrastim prophylaxis in the sample was 4.8 days. The mean duration of pegfilgrastim prophylaxis in the sample was 1.0 day, consistent with the recommended dosage of pegfilgrastim - a single injection once per chemotherapy cycle. Cycles with prophylactic pegfilgrastim were associated with a decreased risk of neutropenia-related hospitalization (narrow definition: OR = 0.43, 95% CI: 0.16-1.13; broad definition: OR = 0.38, 95% CI: 0.24-0.59) and all-cause hospitalization (OR = 0.50, 95% CI: 0.35-0.72) versus cycles with prophylactic filgrastim. For neutropenia-related utilization by setting of care, there were more ambulatory visits and hospitalizations per cycle associated with filgrastim prophylaxis than with pegfilgrastim prophylaxis. Mean per-cycle neutropenia-related costs were also higher with prophylactic filgrastim than with prophylactic pegfilgrastim. In this comparative effectiveness study, pegfilgrastim prophylaxis was associated with a reduced risk of neutropenia-related or all-cause hospitalization relative to filgrastim prophylaxis.

Although not reported to date in patients receiving pegfilgrastim, severe sickle cell crisis (which has been fatal in at least one case) has been reported in patients with sickle cell disease (specifically, homozygous sickle cell anemia, sickle cell-hemoglobin C disease, and sickle cell-beta+-thalassemia disease) who received filgrastim for PBPC mobilization or following chemotherapy. Pegfilgrastim should be used with caution in patients with sickle cell disease, and only after careful consideration of the potential risks and benefits. Patients with sickle cell disease who receive pegfilgrastim should be well hydrated and monitored for the occurrence of sickle cell crisis. If severe sickle cell crisis occurs, supportive care should be initiated, and interventions to ameliorate the underlying event (e.g., therapeutic red blood cell exchange transfusion) should be considered.|Although not reported to date in patients receiving pegfilgrastim, adult respiratory distress syndrome (ARDS) has been reported in neutropenic patients with sepsis receiving filgrastim. It has been postulated that an influx of neutrophils into sites of inflammation in the lungs may have caused such disease. Neutropenic patients receiving pegfilgrastim who develop fever, lung infiltrates, or respiratory distress should be evaluated for the presence of ARDS. If ARDS occurs, pegfilgrastim should be discontinued and/or withheld until ARDS has resolved, and patients should receive appropriate treatment for this condition.|Although not reported to date in patients receiving pegfilgrastim, rare cases of splenic rupture (including some fatalities) have been reported following administration of filgrastim for peripheral blood progenitor cell (PBPC) mobilization in both healthy donors and patients with cancer. Pegfilgrastim has not been evaluated for mobilization of PBPCs and should not be used for this purpose. Patients receiving pegfilgrastim who experience left upper abdominal or shoulder tip pain should be evaluated for the presence of splenomegaly or splenic rupture.|Adverse effects reported in approximately 15-72% of patients receiving pegfilgrastim or filgrastim include nausea, fatigue, alopecia, diarrhea, vomiting, constipation, fever, anorexia, skeletal pain,1 headache, taste perversion, dyspepsia, myalgia, insomnia, abdominal pain, arthralgia, generalized weakness, peripheral edema, dizziness, granulocytopenia, stomatitis, mucositis, and neutropenic fever. These adverse effects generally were attributed to the underlying malignancy or to concomitant cytotoxic chemotherapy. The most common adverse effect attributed to pegfilgrastim in clinical trials was mild-to-moderate medullary bone pain, which occurred in 26% of patients receiving pegfilgrastim and in a comparable percentage of patients receiving filgrastim and resulted in use of opiate or non-opiate analgesics in less than 6 or approximately 12% of those who experienced this adverse effect, respectively.|For more Drug Warnings (Complete) data for Pegfilgrastim (10 total), please visit the HSDB record page.

Compounds that inhibit the activity of DNA TOPOISOMERASE II. Included in this category are a variety of ANTINEOPLASTIC AGENTS which target the eukaryotic form of topoisomerase II and ANTIBACTERIAL AGENTS which target the prokaryotic form of topoisomerase II. (See all compounds classified as Topoisomerase II Inhibitors.)|Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP1A2. (See all compounds classified as Cytochrome P-450 CYP1A2 Inhibitors.)|Substances that inhibit the growth or reproduction of BACTERIA. (See all compounds classified as Anti-Bacterial Agents.)

After subcutaneous administration, pegfilgrastim exhibits nonlinear pharmacokinetics and exposure to pegfilgrastim increases in more than a dose-proportional manner, suggesting that the clearance of pegfilgrastim decreases with increased dosing. Filgrastim is primarily eliminated by the kidney and neutrophils/neutrophil precursors; the latter presumably involves binding of the growth factor to the G-CSF receptor on the cell surface, internalization of the growth factor-receptor complexes via endocytosis, and subsequent degradation inside the cells. Pegylation of filgrastim renders renal clearance insignificant, which was demonstrated in bilaterally nephrectomized rats and confirmed in subjects with renal impairment. As a result, the neutrophil-mediated clearance is the predominant elimination pathway for pegfilgrastim. During chemotherapy-induced neutropenia, the clearance of pegfilgrastim is significantly reduced and the concentration of pegfilgrastim is sustained until onset of neutrophil recovery. Pegfilgrastim concentrations are sustained longer in patients with profound neutropenia. Evidence supports the use of a postnadir absolute neutrophil count (ANC) of > or = 1x109/L as a surrogate marker threshold for the clearance of pegfilgrastim to subtherapeutic levels. After repeated administration of pegfilgrastim, the peak concentrations of pegfilgrastim decrease, likely due to increased neutrophil and neutrophil precursor mass. A pharmacokinetic-pharmacodynamic model was developed to describe the pharmacokinetic and ANC profiles of pegfilgrastim; the analysis supported that 100 ug/kg was an adequate weight-based dose of pegfilgrastim and predicted that 6 mg would be an optimal fixed dose of pegfilgrastim to simplify treatment. Data from a pivotal study confirmed that a once-per-chemotherapy-cycle injection of pegfilgrastim at 6 mg was as safe and effective as 11 daily injections of filgrastim at 5 ug/kg in reducing neutropenia and its complications in patients with breast cancer receiving four cycles of doxorubicin/docetaxel chemotherapy. Because of the highly efficient regulation of pegfilgrastim clearance via neutrophils and neutrophil precursors, a single fixed dose of pegfilgrastim can be given once per chemotherapy cycle in conjunction with a variety of myelosuppressive chemotherapy regimens.|The pharmacokinetics of pegfilgrastim were studied in 379 patients with cancer. The pharmacokinetics of pegfilgrastim were nonlinear and clearance decreased with increases in dose. Neutrophil receptor binding is an important component of the clearance of pegfilgrastim, and serum clearance is directly related to the number of neutrophils. In addition to numbers of neutrophils, body weight appeared to be a factor. Patients with higher body weights experienced higher systemic exposure to pegfilgrastim after receiving a dose normalized for body weight. A large variability in the pharmacokinetics of pegfilgrastim was observed.|Pegfilgrastim is a granulocyte colony-stimulating factor (G-CSF) with a long half-life and sustained duration of action. Pegfilgrastim is created with pegylation technology, whereby a 20-kD polyethylene glycol moiety is conjugated to filgrastim (recombinant human G-CSF), resulting in a larger molecule. Consequently, its renal clearance by glomerular filtration is minimized, making neutrophil-mediated clearance the predominant route of elimination. Preclinical animal data have shown that the clearance of pegfilgrastim depends on dosage and absolute neutrophil count, with pegfilgrastim having a longer circulating half-life and more sustained duration of action than filgrastim. The biologic effect of pegfilgrastim is prolonged in a neutropenic setting because few mature neutrophils are available to mediate its elimination. Clinical trials have suggested that neutrophil-mediated clearance of pegfilgrastim may be self-regulating and may therefore be specific to each patient's hematopoietic recovery.

The half-life of Neulasta ranged from 15 to 80 hours after subcutaneous injection.

Pegfilgrastim is a colony-stimulating factor that acts on hematopoietic cells by binding to specific cell surface receptors, thereby stimulating proliferation, differentiation, commitment, and end cell functional activation.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/CASE REPORTS/ A 77-year-old woman with M2 acute myeloid leukemia was treated with chemotherapy as well as broad-spectrum antibiotics and antifungal drugs because of febrile neutropenia. Ten days after a single dose of pegfilgrastim, she developed a limited number of purple plaques on the neck, left leg, both arms and several indurated and slightly mobile nodules on her forearms. Skin biopsy of a plaque showed a diffused dermal neutrophilic infiltrate with dermal edema. Biopsy of a nodule showed a lobular neutrophilic panniculitis without vasculitis. No foreign material was found in those biopsies. No organisms were detected in blood, urine or tissue cultures. She was started with prednisolone 40 mg once a day, with dramatic improvement within the next 2 days. This case is noteworthy for the simultaneous appearance of Sweet's syndrome and neutrophilic panniculitis and it is the first case of neutrophilic panniculitis associated with this drug, pegfilgrastim.|/CASE REPORTS/ A 3-year-old boy with medulloblastoma therapy presented with white blood cell (WBC) count 0.1 x 10(3)/uL and absolute neutrophil count (ANC) 0.014 x 10(3)/uL on day 27 following a course of induction chemotherapy. The patient received pegfilgrastim 200 ug/kg the following day. On his return 6 days later for the next planned course of chemotherapy, hyperleukocytosis was determined, with WBC 149 x 10(3)/uL and ANC 110 x 10(3)/uL ("neutrophil overshoot"). No sources of the elevated WBC count other than administration of pegfilgrastim (eg, steroids, antiepileptics, infection) were present. Chemotherapy was delayed until the WBC count had fallen to 35.2 x 10(3)/uL (ANC 28.9 x 10(3)/uL). No sequelae from this adverse effect occurred. Pegfilgrastim has unique saturable neutrophil receptor-mediated clearance, the ability for self-regulation. Due to this clearance mechanism, hyperleukocytosis associated with pegfilgrastim use is uncommon in adults and has not been previously reported in pediatrics. The pegfilgrastim dose in children is under investigation; however, 100-110 ug/kg has been effective and safe in this population. Use of the Naranjo probability scale suggested that pegfilgrastim was the probable cause of hyperleukocytosis in our patient. Pegfilgrastim 200 ug/kg, in excess of the 100 ug/kg dose used in limited pediatric clinical trials, appeared to exceed saturable neutrophil receptor-mediated clearance. The inability of this mechanism to self-regulate neutrophil counts in the normal range led to neutrophil overshoot. Routine pediatric use of the pegylated dosage form of G-CSF should await further published clinical trials to validate a safe and effective dose.|/CASE REPORTS/ A 51-year-old white female with a history of breast cancer presented to the hospital with nausea, vomiting and dark urine 2 weeks after her third cycle of cyclophosphamide and docetaxel along with pegfilgrastim. She was found to have AKI with a serum creatinine (Cr) level of 6.9 mg/dL (baseline 0.7). At that time, her AKI was believed to be related to prior sepsis and/or daptomycin exposure that had occurred 5 weeks earlier. She was dialyzed for 6 weeks, after which her kidney function recovered to near baseline, but her urinalysis (UA) still showed 3.5 g protein/day and dysmorphic hematuria. Repeat blood cultures and serological workup (complement levels, hepatitis panel, ANA, ANCA and anti-GBM) were negative. She received her next cycle of chemotherapy with the same drugs. Two weeks later, she developed recurrent AKI with a Cr level of 6.7 mg/dL. A kidney biopsy showed mesangioproliferative GN, along with tubular epithelial damage and a rare electron-dense glomerular deposit. Pegfilgrastim was suspected as the inciting agent after exclusion of other causes. Her Cr improved to 1.4 mg/dL over the next 3 weeks, this time without dialysis. She had the next 2 cycles of chemotherapy without pegfilgrastim, with no further episodes of AKI. A literature review revealed a few cases of a possible association of filgrastim with mild self-limited acute GN. In conclusion, pegfilgrastim may cause GN with severe AKI. Milder cases may be missed and therefore routine monitoring of renal function and UA is important.|/CASE REPORTS/ A 59 years-old man with a stage III-B peripheral T lymphoma with CD4 expression /is reported/. Dose-dense chemotherapy was started with CHOP-14 combined with pegfilgrastim as primary prophylaxis. An error in the dispensing system meant that the patient received pegfilgrastim for 4 consecutive days. He remained under observation in hospital. During the 3 days after the last dose of pegfilgrastim, the patient remained stable, with no remarkable symptoms or associated laboratory abnormalities, and was discharged.

2589 R.B.

Parenteral: Injection, for subcutaneous use: 6 mg/0.6 mL Neulasta (available in prefilled disposable syringes) Amgen.

A covalent conjugate of recombinant methionyl human G-CSF (filgrastim) and monomethoxypropylene glycol ... 175 amino acid proteins|3-Hydroxypropyl-N-methionyl-colony-stimulating factor (human) ...