Neupogen

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using filgrastim and call your doctor at once if you have:

• sudden or severe pain in your left upper stomach spreading up to your shoulder;
• rapid breathing or feeling short of breath;
• kidney problems--little or no urinating, blood in your urine, swelling in your face or your feet and ankles; or
• signs of infection--fever, chills, sore throat, flu symptoms, easy bruising or bleeding (nosebleeds, bleeding gums), loss of appetite, nausea and vomiting, mouth sores, unusual weakness.

Common side effects may include:

• nausea, vomiting;
• muscle or joint pain;
• bone pain; or
• headache.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Neupogen is a prescription medication used to reduce the risk of infection in people with some tumors receiving strong chemotherapy that decreases the number of infection-fighting white blood cells known as neutrophils.

Neupogen belongs to a group of drugs called colony stimulating factors, which stimulate the body to produce neutrophils.

This medication comes in an injectable form that is given just under the skin or directly into a vein (IV), usually once a day.

Common side effects include bone pain and muscle pain.

• Amgen Inc

Serious side effects can occur with Neupogen use. See "Neupogen Precautions".

The most common side effect is aching in the bones and muscles. This aching can usually be relieved by taking a non-aspirin pain reliever such as acetaminophen.

Some people experience redness, swelling, or itching at the site of injection. This may be an allergy to the ingredients in Neupogen, or it may be a local reaction. If you are giving an injection to a child, look for signs of redness, swelling, or itching at the site of injection because they may not be able to tell you they are experiencing a reaction. If you notice any signs of a local reaction, call your doctor.

Tell your doctor if you are allergic to Neupogen or any other ingredient in it.

Tell your doctor about all of your medical conditions, especially if you have any diseases of the blood.

Tell your doctor if you are pregnant or breastfeeding.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

In this monograph, unless otherwise stated, the term “filgrastim products” refers to filgrastim (the reference drug), filgrastim-sndz (the biosimilar), or both drugs.

Biosynthetic (recombinant DNA origin) hematopoietic agents that principally affect the proliferation and differentiation of neutrophils within the bone marrow1 3 4 12 76 78 79 80 81 82 113 145 and possibly other sites (e.g., spleen).23 42 105 113 Exert same pharmacologic effects as endogenous granulocyte colony-stimulating factor (G-CSF).1 3 4 12 76 78 79 80 81 82 113

Filgrastim-sndz is biosimilar to filgrastim (Neupogen).164 165 169 200 A biosimilar is a biological that is highly similar to an FDA-licensed reference biological with the exception of minor differences in clinically inactive components and for which there are no clinically meaningful differences in safety, purity, or potency.163 165 166 Biosimilars are approved through an abbreviated licensure pathway that establishes biosimilarity between proposed biological and reference biological but does not independently establish safety and effectiveness of the proposed biological.163 166 170 Filgrastim-sndz is considered a therapeutic alternative to filgrastim; not interchangeable.168 169

Filgrastim and tbo-filgrastim are structurally and pharmacologically similar and contain a related drug substance.1 145 151 155 Tbo-filgrastim was licensed by FDA through a biologics license application (BLA), not as a biosimilar to filgrastim;155 at the time of tbo-filgrastim's submission for approval, FDA had not finalized a process for approving biosimilars.151 153 154 155

ASCO states that choice of a G-CSF (e.g., filgrastim, filgrastim-sndz, tbo-filgrastim) for the treatment of febrile neutropenia should be determined based upon convenience, cost, and the clinical situation.171

It is very important that your doctor check the progress of you or your child at regular visits to make sure this medicine is working properly. Blood and urine tests may be needed to check for unwanted effects.

Check with your doctor right away at the first sign of an infection, such as fever, chills, cough, sore throat, or unusual tiredness or weakness.

This medicine may cause serious allergic reactions, including anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Tell your doctor right away if you or your child has a rash, itching skin, dizziness, lightheadedness, or fainting, swelling of the face, tongue, or throat, trouble breathing, or chest pain after you receive the medicine.

Check with your doctor right away if you or your child are having pain in the upper left part of your stomach or at the tip of the left shoulder. This could be a symptom of a serious side effect with the spleen.

Check with your doctor right away if you or your child develop a fever, chest pain or tightness, or trouble breathing. These could be symptoms of a serious lung condition called acute respiratory distress syndrome (ARDS).

This medicine may cause bleeding in the lungs. Check with your doctor right away if you or your child cough up blood or have blood in your sputum (spit).

This medicine may cause kidney problems. Call your doctor right away if you or your child has swelling in your face or ankles, blood in the urine, or decrease in how much or how often you urinate.

This medicine may cause a condition called capillary leak syndrome. It can cause fluid to leak from the blood vessels into your body's tissues. Call your doctor right away if you have swelling or puffiness and are urinating less often, trouble breathing, feeling of fullness, dizziness, or feeling faint.

Check with your doctor right away if you or your child has black or tarry stools, bleeding gums, blood in the urine or stools, pinpoint red spots on the skin, or unusual bleeding or bruising after receiving this medicine.

The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex). This may cause an allergic reaction in people who are sensitive to latex. Tell your doctor if you or your child has a latex allergy before you start using this medicine.

Before you have any medical tests, tell the medical doctor in charge that you are using this medicine. The results of some tests may be affected by this medicine.

• It is used to lower the chance of getting an infection in people with bone marrow problems caused by chemo.
• It is used to raise the number of white blood cells in certain patients.
• It is used in patients who have been exposed to certain doses of radiation.
• It may be given to you for other reasons. Talk with the doctor.

• If you have an allergy to filgrastim or any other part of Neupogen (filgrastim injection).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as a shot into the fatty part of the skin.
• It may be given as a shot into a vein.
• To gain the most benefit, do not miss doses.
• Keep taking Neupogen as you have been told by your doctor or other health care provider, even if you feel well.
• If you will be giving yourself the shot, your doctor or nurse will teach you how to give the shot.
• Follow how to use as you have been told by the doctor or read the package insert.
• Before using this medicine, take it out of the refrigerator and leave it at room temperature for 30 minutes.
• Do not use if the solution is cloudy, leaking, or has particles.
• Do not use if solution changes color.
• Do not shake the solution.
• Wash your hands before and after you give the shot.
• Do not give into skin that is irritated, bruised, red, infected, or scarred.
• Move the site where you give the shot with each shot.
• Throw away any part left over after the dose is given.
• Throw syringe away after use. Do not use the same syringe more than one time.
• Throw away needles in a needle/sharp disposal box. Do not reuse needles or other items. When the box is full, follow all local rules for getting rid of it. Talk with a doctor or pharmacist if you have any questions.
• Do not switch between different brands of Neupogen without first talking with the doctor.
• Do not switch between different forms of this medicine without first talking with the doctor.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Back pain.
• Bone pain.
• Joint pain.
• Cough.
• Headache.
• Upset stomach.
• Feeling tired or weak.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

8.1       Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. The potential risk to the fetus is unknown. Reports in the scientific literature have described transplacental passage of Neupogen in pregnant women when administered ≤ 30 hours prior to preterm delivery (≤ 30 weeks gestation). Neupogen should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Effects of filgrastim on prenatal development have been studied in rats and rabbits. No malformations were observed in either species. Filgrastim has been shown to have adverse effects in pregnant rabbits at doses 2 to 10 times higher than the human doses. In pregnant rabbits showing signs of maternal toxicity, reduced embryo-fetal survival (at 20 and 80 mcg/kg/day) and increased abortions (at 80 mcg/kg/day) were observed. In pregnant rats, no maternal or fetal effects were observed at doses up to 575 mcg/kg/day.

Offspring of rats administered filgrastim during the peri-natal and lactation periods exhibited a delay in external differentiation and growth retardation (≥ 20 mcg/kg/day) and slightly reduced survival rate (100 mcg/kg/day).

8.3       Nursing Mothers

It is not known whether Neupogen is excreted in human milk.  Because many drugs are excreted in human milk‚ caution should be exercised if Neupogen is administered to women who are breastfeeding.

8.4       Pediatric Use

In patients with cancer receiving myelosuppressive chemotherapy‚ 15 pediatric patients median age 2.6 (range 1.2 to 9.4) years with neuroblastoma were treated with myelosuppressive chemotherapy (cyclophosphamide‚ cisplatin‚ doxorubicin‚ and etoposide) followed by subcutaneous Neupogen at doses of 5, 10, or 15 mcg/kg/day for 10 days (n = 5/dose) (Study 8).  The pharmacokinetics of Neupogen in pediatric patients after chemotherapy are similar to those in adults receiving the same weight-normalized doses, suggesting no age-related differences in the pharmacokinetics of Neupogen. In this population‚ Neupogen was well tolerated. There was one report of palpable splenomegaly and one report of hepatosplenomegaly associated with Neupogen therapy; however‚ the only consistently reported adverse event was musculoskeletal pain‚ which is no different from the experience in the adult population.

The safety and effectiveness of Neupogen have been established in pediatric patients with SCN [see Clinical Studies (14.5)].  In a phase 3 study (Study 7) to assess the safety and efficacy of Neupogen in the treatment of SCN, 123 patients with a median age of 12 years (range 7 months to 76 years) were studied. Of the 123 patients, 12 were infants (7 months to 2 years of age), 49 were children (2 to 12 years of age), and 9 were adolescents (12 to 16 years of age). Additional information is available from a SCN postmarketing surveillance study, which includes long-term follow-up of patients in the clinical studies and information from additional patients who entered directly into the postmarketing surveillance study. Of the 731 patients in the surveillance study, 429 were pediatric patients < 18 years of age (range 0.9 to 17) [see Indications and Usage (1.5), Dosage and Administration (2.6), and Clinical Studies (14.5)].

Long-term follow-up data from the postmarketing surveillance study suggest that height and weight are not adversely affected in patients who received up to 5 years of Neupogen treatment. Limited data from patients who were followed in the phase 3 study for 1.5 years did not suggest alterations in sexual maturation or endocrine function.

Pediatric patients with congenital types of neutropenia (Kostmann’s syndrome, congenital agranulocytosis, or Schwachman-Diamond syndrome) have developed cytogenetic abnormalities and have undergone transformation to MDS and AML while receiving chronic Neupogen treatment. The relationship of these events to Neupogen administration is unknown [see Warnings and Precautions (5.8) and Adverse Reactions (6)].

The use of Neupogen to increase survival in pediatric patients acutely exposed to myelosuppressive doses of radiation is based on studies conducted in animals and clinical data supporting the use of Neupogen in other approved indications [see Dosage and Administration (2.1 to 2.4) and Clinical Studies (14.6)].

8.5       GERIATRIC USE

Among 855 subjects enrolled in 3 randomized, placebo-controlled trials of Neupogen-treated patients receiving myelosuppressive chemotherapy, there were 232 subjects age 65 or older, and 22 subjects age 75 or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Clinical studies of Neupogen in other approved indications (i.e., BMT recipients, PBPC mobilization, and SCN) did not include sufficient numbers of subjects aged 65 and older to determine whether elderly subjects respond differently from younger subjects.

Neupogen (filgrastim) is a 175 amino acid human granulocyte colony-stimulating factor (G-CSF) manufactured by recombinant DNA technology. Neupogen is produced by Escherichia coli (E coli) bacteria into which has been inserted the human granulocyte colony-stimulating factor gene. Neupogen has a molecular weight of 18‚800 daltons. The protein has an amino acid sequence that is identical to the natural sequence predicted from human DNA sequence analysis‚ except for the addition of an N-terminal methionine necessary for expression in E coli. Because Neupogen is produced in E coli‚ the product is non-glycosylated and thus differs from G-CSF isolated from a human cell.

Neupogen injection is a sterile‚ clear‚ colorless‚ preservative-free liquid containing filgrastim at a specific activity of 1.0 ± 0.6 x 108 U/mg (as measured by a cell mitogenesis assay). The product is available in single-dose vials and prefilled syringes. The single-dose vials contain either 300 mcg/mL or 480 mcg/1.6 mL of filgrastim. The single-dose prefilled syringes contain either 300 mcg/0.5 mL or 480 mcg/0.8 mL of filgrastim. See table below for product composition of each single-dose vial or prefilled syringe.

* quantity sufficient to make

12.1       Mechanism of Action

Colony-stimulating factors are glycoproteins which act on hematopoietic cells by binding to specific cell surface receptors and stimulating proliferation‚ differentiation commitment‚ and some end-cell functional activation.

Endogenous G-CSF is a lineage-specific colony-stimulating factor that is produced by monocytes‚ fibroblasts, and endothelial cells. G-CSF regulates the production of neutrophils within the bone marrow and affects neutrophil progenitor proliferation‚ differentiation, and selected end-cell functions (including enhanced phagocytic ability‚ priming of the cellular metabolism associated with respiratory burst‚ antibody-dependent killing, and the increased expression of some cell surface antigens). G-CSF is not species-specific and has been shown to have minimal direct in vivo or in vitro effects on the production or activity of hematopoietic cell types other than the neutrophil lineage.

12.2       Pharmacodynamics

In phase 1 studies involving 96 patients with various nonmyeloid malignancies‚ Neupogen administration resulted in a dose-dependent increase in circulating neutrophil counts over the dose range of 1 to 70 mcg/kg/day. This increase in neutrophil counts was observed whether Neupogen was administered intravenous (1 to 70 mcg/kg twice daily)‚ subcutaneous (1 to 3 mcg/kg once daily)‚ or by continuous subcutaneous infusion (3 to 11 mcg/kg/day). With discontinuation of Neupogen therapy‚ neutrophil counts returned to baseline in most cases within 4 days. Isolated neutrophils displayed normal phagocytic (measured by zymosan-stimulated chemoluminescence) and chemotactic (measured by migration under agarose using N-formyl-methionyl-leucyl-phenylalanine [fMLP] as the chemotaxin) activity in vitro.

The absolute monocyte count was reported to increase in a dose-dependent manner in most patients receiving Neupogen; however‚ the percentage of monocytes in the differential count remained within the normal range. Absolute counts of both eosinophils and basophils did not change and were within the normal range following administration of Neupogen. Increases in lymphocyte counts following Neupogen administration have been reported in some normal subjects and patients with cancer.

White blood cell (WBC) differentials obtained during clinical trials have demonstrated a shift towards earlier granulocyte progenitor cells (left shift)‚ including the appearance of promyelocytes and myeloblasts‚ usually during neutrophil recovery following the chemotherapy-induced nadir. In addition‚ Dohle bodies‚ increased granulocyte granulation‚ and hypersegmented neutrophils have been observed. Such changes were transient and were not associated with clinical sequelae, nor were they necessarily associated with infection.

12.3       Pharmacokinetics

Filgrastim exhibits nonlinear pharmacokinetics.  Clearance is dependent on filgrastim concentration and neutrophil count: G-CSF receptor-mediated clearance is saturated by high concentration of Neupogen and is diminished by neutropenia.  In addition, filgrastim is cleared by the kidney.

Subcutaneous administration of 3.45 mcg/kg and 11.5 mcg/kg of filgrastim resulted in maximum serum concentrations of 4 and 49 ng/mL‚ respectively‚ within 2 to 8 hours. After intravenous administration, the volume of distribution averaged 150 mL/kg and the elimination half-life was approximately 3.5 hours in both normal subjects and cancer subjects. Clearance rates of filgrastim were approximately 0.5 to 0.7 mL/minute/kg. Single parenteral doses or daily intravenous doses‚ over a 14-day period‚ resulted in comparable half-lives. The half-lives were similar for intravenous administration (231 minutes‚ following doses of 34.5 mcg/kg) and for subcutaneous administration (210 minutes‚ following Neupogen dosages of 3.45 mcg/kg). Continuous 24-hour intravenous infusions of 20 mcg/kg over an 11 to 20-day period produced steady-state serum concentrations of filgrastim with no evidence of drug accumulation over the time period investigated. The absolute bioavailability of filgrastim after subcutaneous administration is 60% to 70%.  

Specific Populations

Patients Acutely Exposed to Myelosuppressive Doses of Radiation

The pharmacokinetics of filgrastim is not available in patients acutely exposed to myelosuppressive doses of radiation.  Based on limited pharmacokinetics data in irradiated non-human primates, the area under the time-concentration curve (AUC), reflecting the exposure to filgrastim in non-human primates at 10 mcg/kg dose of Neupogen, appears to be similar to that in humans at 5 mcg/kg.  Simulations conducted using the population pharmacokinetic model indicates that the exposures to filgrastim at a Neupogen dose of 10 mcg/kg in patients acutely exposed to myelosuppressive doses of radiation are expected to exceed the exposures at a dose of 10 mcg/kg in irradiated non-human primates.

Pediatric Patients

The pharmacokinetics of filgrastim in pediatric patients after chemotherapy are similar to those in adult patients receiving the same weight-normalized doses, suggesting no age-related differences in the pharmacokinetics of filgrastim [see Use in Specific Populations (8.4)].

Renal Impairment

In a study with healthy volunteers, subjects with moderate renal impairment, and subjects with end-stage renal disease (n = 4 per group), higher serum concentrations were observed in subjects with end-stage renal disease. However, dose adjustment in patients with renal impairment is not necessary.

Hepatic Impairment

Pharmacokinetics and pharmacodynamics of filgrastim are similar between subjects with hepatic impairment and healthy subjects (n = 12/group). The study included 10 subjects with mild hepatic impairment (Child-Pugh Class A) and 2 subjects with moderate hepatic impairment (Child-Pugh Class B).  Therefore, filgrastim dose adjustment for patients with hepatic impairment is not necessary.