Neulasta Drug Information

Patients with Cancer Receiving Myelosuppressive Chemotherapy Neulasta is indicated in adult and pediatric patients to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Limitations of Use Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Patients with Hematopoietic Subsyndrome of Acute Radiation Syndrome Neulasta is indicated to increase survival in adults and pediatric patients acutely exposed to myelosuppressive doses of radiation.

Patients with Cancer Receiving Myelosuppressive Chemotherapy

The recommended dosage of Neulasta 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. For dosing in pediatric patients weighing less than 45 kg, refer to Table 1. Do not administer Neulasta between 14 days before and 24 hours after administration of chemotherapy.

Table 1. Dosing of Neulasta for Pediatric Patients Weighing Less Than 45 kg

Patients with Hematopoietic Subsyndrome of Acute Radiation Syndrome The recommended dosage of Neulasta 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 Neulasta 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.

Preparation and Administration Neulasta is supplied in single-dose prefilled syringes for manual use or for use with the on-body injector (OBI) for Neulasta, which is co-packaged with a single-dose prefilled syringe for the OBI, and in single-dose vials. Before using any of the Neulasta presentations: Remove the carton from the refrigerator and allow the Neulasta prefilled syringe or vial to reach room temperature, 20°C to 25°C (68°F to 77°F), for a minimum of 30 minutes. Do not warm in any other way.

Discard any prefilled syringe or vial left at room temperature for greater than 48 hours. Neulasta is a clear, colorless, preservative-free solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Do not administer Neulasta 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 Neulasta. The syringe does not bear graduation marks and therefore does not allow for direct administration of doses less than 6 mg/0.6 mL.

The needle cap on the prefilled syringe contains dry natural rubber (derived from latex); persons with latex allergies should not administer this product. The prefilled syringe co-packaged in the Neulasta Onpro ® kit must only be used with the OBI for Neulasta. Use of the OBI for Neulasta is not recommended for patients with hematopoietic subsyndrome of acute radiation syndrome.

Use of the OBI for Neulasta has not been studied in pediatric patients. Vial For pediatric patients weighing less than 45 kg, the dose is prepared by withdrawing the required volume from the 4 mg/0.4 mL single-dose vial. A 0.5 mL staked tuberculin syringe with 0.01 mL graduation marks is recommended for preparation and administration for dose accuracy.

Only healthcare providers should prepare and administer doses from the vials. Administer Neulasta subcutaneously. Discard unused portion of Neulasta in vials.

Do not save unused drug for later administration.

Special Healthcare Provider Instructions for the On-body Injector for Neulasta A healthcare provider must fill the on-body injector (OBI) with Neulasta using the prefilled syringe and then apply the OBI for Neulasta to the patient's skin (abdomen or back of arm). The back of the arm may only be used if there is a caregiver available to monitor the status of the OBI for Neulasta. Approximately 27 hours after the OBI for Neulasta is applied to the patient's skin, Neulasta will be delivered over approximately 45 minutes.

A healthcare provider may initiate administration with the OBI for Neulasta on the same day as the administration of chemotherapy, as long as the OBI for Neulasta delivers Neulasta no less than 24 hours after administration of chemotherapy. The prefilled syringe contains additional solution to compensate for liquid loss during delivery through the OBI for Neulasta. If the prefilled syringe co-packaged in Neulasta Onpro kit is used for manual subcutaneous injection, the patient will receive an overdose.

If the prefilled syringe for manual use is used with the OBI for Neulasta, the patient may receive less than the recommended dose. Do not use the OBI for Neulasta to deliver any other drug product except the Neulasta prefilled syringe co-packaged with the OBI for Neulasta. The OBI for Neulasta should be applied to intact, non-irritated skin on the arm or abdomen.

A missed dose could occur due to an OBI for Neulasta failure or leakage. If the patient misses a dose, a new dose should be administered by prefilled syringe for manual use, as soon as possible after detection. Refer to the Healthcare Provider Instructions for Use for the OBI for Neulasta for full administration information.

Advice to Give to Patients Regarding

Administration via the On-body Injector for Neulasta Advise patients to avoid activities such as traveling, driving, or operating heavy machinery during hours 26-29 following application of the on-body injector (OBI) for Neulasta (this includes the 45-minute delivery period plus an hour post-delivery). Patients should have a caregiver nearby for the first use. Refer the patient to the dose delivery information written on the Patient Instructions for Use.

Provide training to patients to ensure they understand when the dose delivery of Neulasta will begin and how to monitor the OBI for Neulasta for completed delivery. Ensure patients understand how to identify signs of malfunction of OBI for Neulasta. Instruct patients using the OBI to notify their healthcare professional immediately in order to determine the need for a replacement dose of Neulasta if they suspect that the device may not have performed as intended.

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. Neulasta clinical trials safety data are based upon 932 patients receiving Neulasta in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female.

Patients with breast (n = 823), lung and thoracic tumors (n = 53) and lymphoma (n = 56) received Neulasta after nonmyeloablative cytotoxic chemotherapy. The patients were 21 to 88 years of age and 99% female. 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 2. No complications attributable to leukocytosis were reported in clinical studies.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Neulasta. 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) Acute respiratory distress syndrome (ARDS) Allergic reactions/hypersensitivity, including anaphylaxis, skin rash, urticaria, generalized erythema, and flushing Sickle cell crisis Glomerulonephritis Leukocytosis Thrombocytopenia Capillary Leak Syndrome Injection site reactions Sweet's syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis Application site reactions (including events such as application site hemorrhage, application site pain, application site discomfort, application site bruise, and application site erythema) have been reported with the use of the on-body injector for Neulasta.

Contact dermatitis and local skin reactions such as rash, pruritus, and urticaria have been reported with the use of the on-body injector for Neulasta, possibly indicating a hypersensitivity reaction to the adhesive. Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with breast and lung cancer receiving chemotherapy and/or radiotherapy Large and medium vessel arteritis, including aortitis Alveolar hemorrhage

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

Efficacy studies of Neulasta 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 Neulasta (Table 1), administered one week apart provide pediatric patients with exposures comparable to that in adults receiving two 6 mg doses one week apart.

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

Overdosage of Neulasta may result in leukocytosis and bone pain. Events of edema, dyspnea, and pleural effusion have been reported in a single patient who administered Neulasta 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.