Ziextenzo Drug Information

• Patients with cancer receiving myelosuppressive chemotherapy
• For adult patients of any weight and pediatric patients weighing 45 kg and greater, the recommended dosage is 6 mg subcutaneously once per chemotherapy cycle. ( 2.1 )
• Do not administer between 14 days before and 24 hours after administration of chemotherapy. ( 2.1 ) Patients acutely exposed to myelosuppressive doses of radiation
• For adults of any weight and pediatric patients weighing 45 kg and greater, the recommended dosage is two doses, 6 mg each, subcutaneously one week apart. Administer the first dose as soon as possible after suspected or confirmed exposure to myelosuppressive doses of radiation, and a second dose one week after. ( 2.2 ) 2.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy The recommended dosage of ZIEXTENZO for adults of any weight and pediatric patients weighing at least 45 kg with cancer receiving myelosuppressive chemotherapy is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle. Do not administer ZIEXTENZO between 14 days before and 24 hours after administration of chemotherapy. 2.2 Patients with Hematopoietic Subsyndrome of Acute Radiation Syndrome The recommended dosage of ZIEXTENZO for adults of any weight and pediatric patients weighing at least 45 kg with hematopoietic subsyndrome of acute radiation syndrome is two doses, 6 mg each, administered subcutaneously one week apart. Administer the first dose as soon as possible after suspected or confirmed exposure to radiation levels greater than 2 gray (Gy). Administer the second dose one week after the first dose. Obtain a baseline complete blood count (CBC). Do not delay administration of ZIEXTENZO if a CBC is not readily available. Estimate a patient’s absorbed radiation dose (i.e., level of radiation exposure) based on information from public health authorities, biodosimetry if available, or clinical findings such as time to onset of vomiting or lymphocyte depletion kinetics. 2.3 Preparation and Administration ZIEXTENZO is supplied as single-dose prefilled syringe for manual use [see Dosage Forms and Strengths ( 3 )]. Before using ZIEXTENZO:
• Remove the carton from the refrigerator and allow the ZIEXTENZO prefilled syringe to reach room temperature, 20 ° C to 25 ° C (68 ° F to 77 ° F) for a minimum of 15-30 minutes. Do not warm in any other way. Discard any prefilled syringe left at temperatures between 20°C to 35°C (68°F to 95°F) for greater than 120 hours.
• ZIEXTENZO is a clear, colorless to slightly yellowish solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer ZIEXTENZO if discoloration or particulates are observed. Prefilled Syringe for Manual Use For adult patients of any weight and pediatric patients weighing 45 kg and greater, the single-dose prefilled syringe for manual use is intended for subcutaneous administration of a single 6 mg/0.6 mL dose of ZIEXTENZO. The syringe does not bear graduation marks and therefore does not allow for direct administration of doses less than 6 mg/0.6 mL. There is no presentation for ZIEXTENZO that allows weight-based dosing for pediatric patients below 45 kg. The ZIEXTENZO syringe plunger stopper and needle cap are not made with natural rubber latex.

• The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
• Splenic Rupture [see Warnings and Precautions ( 5.1 )]
• Acute Respiratory Distress Syndrome [see Warnings and Precautions ( 5.2 )]
• Serious Hypersensitivity Reactions [see Warnings and Precautions ( 5.3 )]
• Use in Patients with Sickle Cell Disorders [see Warnings and Precautions ( 5.4 )]
• Glomerulonephritis [see Warnings and Precautions ( 5.5 )]
• Leukocytosis [see Warnings and Precautions ( 5.6 )]
• Thrombocytopenia [see Warnings and Precautions ( 5.7 )]
• Capillary Leak Syndrome [see Warnings and Precautions ( 5.8 )]
• Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions ( 5.9 )]
• Myelodysplastic syndrome [see Warnings and Precautions ( 5.10 )]
• Acute myeloid leukemia [see Warnings and Precautions ( 5.10 )]
• Aortitis [see Warnings and Precautions ( 5.11 )] Most common adverse reactions (≥ 5% difference in incidence compared to placebo) are bone pain and pain in extremity. ( 6.1 ) *Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of ZIEXTENZO has been demonstrated for the condition(s) of use (e.g., indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information. To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Pegfilgrastim clinical trials safety data are based upon 932 patients receiving pegfilgrastim in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. Patients with breast (n = 823), lung and thoracic tumors (n = 53) and lymphoma (n = 56) received pegfilgrastim after nonmyeloablative cytotoxic chemotherapy. Most patients received a single 100 mcg/kg (n = 259) or a single 6 mg (n = 546) dose per chemotherapy cycle over 4 cycles. The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients with metastatic or non-metastatic breast cancer receiving docetaxel 100 mg/m 2 every 21 days (Study 3). A total of 928 patients were randomized to receive either 6 mg pegfilgrastim (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and < 1% Asian, Native American, or other. The most common adverse reactions occurring in ≥ 5% of patients and with a between-group difference of ≥ 5% higher in the pegfilgrastim arm in placebo-controlled clinical trials are bone pain and pain in extremity. Table 1. Adverse Reactions with ≥ 5% Higher Incidence in Pegfilgrastim Patients Compared to Placebo in Study 3 Body System Adverse Reaction Placebo (N = 461) Pegfilgrastim 6 mg SC on Day 2 (N = 467) Musculoskeletal and connective tissue disorders Bone pain 26% 31% Pain in extremity 4% 9% Leukocytosis In clinical studies, leukocytosis (WBC counts > 100 x 10 9 /L) was observed in less than 1% of 932 patients with non-myeloid malignancies receiving pegfilgrastim. No complications attributable to leukocytosis were reported in clinical studies. 6.3 Postmarketing Experience The following adverse reactions have been identified during post approval use of pegfilgrastim products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
• Splenic rupture and splenomegaly (enlarged spleen) [see Warnings and Precautions ( 5.1 )]
• Acute respiratory distress syndrome (ARDS) [see Warnings and Precautions ( 5.2 )]
• Allergic reactions/hypersensitivity, including anaphylaxis, skin rash, urticaria, generalized erythema, and flushing [see Warnings and Precautions ( 5.3 )]
• Sickle cell crisis [see Warnings and Precautions ( 5.4 )]
• Glomerulonephritis [see Warnings and Precautions ( 5.5 )]
• Leukocytosis [see Warnings and Precautions ( 5.6 )]
• Thrombocytopenia [see Warnings and Precautions ( 5.7 )]
• Capillary Leak Syndrome [see Warnings and Precautions ( 5.8 )]
• Injection site reactions
• Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis
• Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with breast and lung cancer receiving chemotherapy and/or radiotherapy [see Warnings and Precautions ( 5.10 )]
• Aortitis [see Warnings and Precautions ( 5.11 )]
• Alveolar hemorrhage

Pregnancy Risk Summary Although available data with pegfilgrastim product use in pregnant women are insufficient to establish whether there is a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, there are available data from published studies in pregnant women exposed to filgrastim products. These studies have not established an association of filgrastim product use during pregnancy with major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, no evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area). In pregnant rabbits, increased embryolethality and spontaneous abortions occurred at 4 times the maximum recommended human dose simultaneously with signs of maternal toxicity (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Pregnant rabbits were dosed with pegfilgrastim subcutaneously every other day during the period of organogenesis.

At cumulative doses ranging from the approximate human dose to approximately 4 times the recommended human dose (based on body surface area), the treated rabbits exhibited decreased maternal food consumption, maternal weight loss, as well as reduced fetal body weights and delayed ossification of the fetal skull; however, no structural anomalies were observed in the offspring from either study. Increased incidences of post-implantation losses and spontaneous abortions (more than half the pregnancies) were observed at cumulative doses approximately 4 times the recommended human dose, which were not seen when pregnant rabbits were exposed to the recommended human dose. Three studies were conducted in pregnant rats dosed with pegfilgrastim at cumulative doses up to approximately 10 times the recommended human dose at the following stages of gestation: during the period of organogenesis, from mating through the first half of pregnancy, and from the first trimester through delivery and lactation.

No evidence of fetal loss or structural malformations was observed in any study. Cumulative doses equivalent to approximately 3 and 10 times the recommended human dose resulted in transient evidence of wavy ribs in fetuses of treated mothers (detected at the end of gestation but no longer present in pups evaluated at the end of lactation).

Pediatric Use The safety and effectiveness of ZIEXTENZO for chemotherapy-induced neutropenia and hematopoietic subsyndrome of acute radiation syndrome have been established in pediatric patients aged newborn and older. Use of ZIEXTENZO in pediatric patients for chemotherapy-induced neutropenia is based on adequate and well-controlled studies of pegfilgrastim in adults with additional pharmacokinetic and safety data of pegfilgrastim in pediatric patients aged 8 months and older with sarcoma. The use of ZIEXTENZO to increase survival in pediatric patients acutely exposed to myelosuppressive doses of radiation is based on efficacy studies of pegfilgrastim conducted in animals and clinical data supporting the use of pegfilgrastim in patients with cancer receiving myelosuppressive chemotherapy.

Efficacy studies of pegfilgrastim products could not be conducted in humans with acute radiation syndrome for ethical and feasibility reasons. Results from population modeling and simulation indicate that two doses of pegfilgrastim, administered one week apart provide pediatric patients with exposures comparable to that in adults receiving two 6 mg doses one week apart.

is contraindicated in patients with a history of a serious hypersensitivity reaction to pegfilgrastim products or filgrastim products. Reactions have included anaphylaxis . In patients with a history of serious hypersensitivity reaction to pegfilgrastim products or filgrastim products.

Overdosage of pegfilgrastim products may result in leukocytosis and bone pain. Events of edema, dyspnea, and pleural effusion have been reported in a single patient who administered pegfilgrastim on 8 consecutive days in error. In the event of overdose, the patient should be monitored for adverse reactions.

Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.