(filgrastim-aafi)

Prescribing Information
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6 ADVERSE REACTIONS

6 ADVERSE REACTIONS

The following serious 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 Allergic Reactions [see Warnings and Precautions (5.3)]
•
Sickle Cell Disorders [see Warnings and Precautions (5.4)]
•
Glomerulonephritis [see Warnings and Precautions (5.5)]
•
Alveolar Hemorrhage and Hemoptysis [see Warnings and Precautions (5.6)]
•
Capillary Leak Syndrome [see Warnings and Precautions (5.7)]
•
Myelodysplastic Syndrome [see Warnings and Precautions (5.8)]
•
Acute Myeloid Leukemia [see Warnings and Precautions (5.8)]
•
Thrombocytopenia [see Warnings and Precautions (5.9)]
•
Leukocytosis [see Warnings and Precautions (5.10)]
•
Cutaneous Vasculitis [see Warnings and Precautions (5.11)]
•
Aortitis [see Warnings and Precautions (5.15)]

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.

Adverse Reactions in Patients with Cancer Receiving Myelosuppressive Chemotherapy

The following adverse reaction data in Table 2 are from three randomized, placebo-controlled studies in patients with:

•
small cell lung cancer receiving standard dose chemotherapy with cyclophosphamide‚ doxorubicin‚ and etoposide (Study 1)
•
small cell lung cancer receiving ifosfamide, doxorubicin‚ and etoposide (Study 2), and
•
non-Hodgkin's lymphoma (NHL) receiving doxorubicin, cyclophosphamide, vindesine, bleomycin, methylprednisolone, and methotrexate ("ACVBP") or mitoxantrone, ifosfamide, mitoguazone, teniposide, methotrexate, folinic acid, methylprednisolone, and methotrexate ("VIM3") (Study 3).

A total of 451 patients were randomized to receive subcutaneous filgrastim 230 mcg/m2 (Study 1), 240 mcg/m2 (Study 2) or 4 or 5 mcg/kg/day (Study 3) (n = 294) or placebo (n = 157). The patients in these studies were median age 61 (range 29 to 78) years and 64% were male. The ethnicity was 95% Caucasian, 4% African American, and 1% Asian.

Table 2. Adverse Reactions in Patients with Cancer Receiving Myelosuppressive Chemotherapy (With ≥ 5% Higher Incidence in Filgrastim Compared to Placebo)
System Organ Class
Preferred Term		Filgrastim
(N = 294)		Placebo
(N = 157)
*
Percent difference (Filgrastim – Placebo) was 4%.

Blood and lymphatic system disorders

  Thrombocytopenia

38%

29%

Gastrointestinal disorders

  Nausea

43%

32%

General disorders and administration site conditions

  Pyrexia

48%

29%

  Chest pain

13%

6%

  Pain

12%

6%

  Fatigue

20%

10%

Musculoskeletal and connective tissue disorders

  Back pain

15%

8%

  Arthralgia

9%

2%

  Bone pain

11%

6%

  Pain in extremity*

7%

3%

Nervous system disorders

  Dizziness

14%

3%

Respiratory, thoracic and mediastinal disorders

  Cough

14%

8%

  Dyspnea

13%

8%

Skin and subcutaneous tissue disorders

  Rash

14%

5%

Investigations

  Blood lactate dehydrogenase increased

6%

1%

  Blood alkaline phosphatase increased

6%

1%

Adverse events with ≥ 5% higher incidence in filgrastim patients compared to placebo and associated with the sequelae of the underlying malignancy or cytotoxic chemotherapy delivered included anemia, constipation, diarrhea, oral pain, vomiting, asthenia, malaise, edema peripheral, hemoglobin decreased, decreased appetite, oropharyngeal pain, and alopecia.

Adverse Reactions in Patients with Acute Myeloid Leukemia

Adverse reaction data below are from a randomized, double-blind, placebo-controlled study in patients with AML (Study 4) who received an induction chemotherapy regimen of intravenous daunorubicin days 1, 2, and 3; cytosine arabinoside days 1 to 7; and etoposide days 1 to 5 and up to 3 additional courses of therapy (induction 2, and consolidation 1, 2) of intravenous daunorubicin, cytosine arabinoside, and etoposide. The safety population included 518 patients randomized to receive either 5 mcg/kg/day filgrastim (n = 257) or placebo (n = 261). The median age was 54 (range 16 to 89) years and 54% were male.

Adverse reactions with ≥ 2% higher incidence in filgrastim patients compared to placebo included epistaxis, back pain, pain in extremity, erythema, and rash maculo-papular.

Adverse events with ≥ 2% higher incidence in filgrastim patients compared to placebo and associated with the sequelae of the underlying malignancy or cytotoxic chemotherapy included diarrhea, constipation, and transfusion reaction.

Adverse Reactions in Patients with Cancer Undergoing Bone Marrow Transplantation

The following adverse reaction data are from one randomized, no treatment-controlled study in patients with acute lymphoblastic leukemia or lymphoblastic lymphoma receiving high-dose chemotherapy (cyclophosphamide or cytarabine, and melphalan) and total body irradiation (Study 5) and one randomized, no treatment-controlled study in patients with Hodgkin's disease (HD) and NHL undergoing high-dose chemotherapy and autologous bone marrow transplantation (Study 6). Patients receiving autologous bone marrow transplantation only were included in the analysis. A total of 100 patients received either 30 mcg/kg/day as a 4-hour infusion (Study 5) or 10 mcg/kg/day or 30 mcg/kg/day as a 24-hour infusion (Study 6) filgrastim (n = 72), no treatment control or placebo (n = 28). The median age was 30 (range 15 to 57) years, 57% were male.

Adverse reactions with ≥ 5% higher incidence in filgrastim patients compared to patients receiving no filgrastim included rash and hypersensitivity.

Adverse reactions in patients receiving intensive chemotherapy followed by autologous BMT with ≥ 5% higher incidence in filgrastim patients compared to patients receiving no filgrastim included thrombocytopenia, anemia, hypertension, sepsis, bronchitis, and insomnia.

Adverse Reactions in Patients with Cancer Undergoing Autologous Peripheral Blood Progenitor Cell Collection

The adverse reaction data in Table 3 are from a series of 7 trials in patients with cancer undergoing mobilization of autologous peripheral blood progenitor cells for collection by leukapheresis. Patients (n = 166) in all these trials underwent a similar mobilization/collection regimen: filgrastim was administered for 6 to 8 days‚ in most cases the apheresis procedure occurred on days 5‚ 6, and 7. The dosage of filgrastim ranged between 5 to 30 mcg/kg/day and was administered subcutaneously by injection or continuous infusion. The median age was 39 (range 15 to 67) years, and 48% were male.

Table 3. Adverse Reactions in Patients with Cancer Undergoing Autologous PBPC in the Mobilization Phase (≥ 5% Incidence in Filgrastim Patients)
System Organ Class
Preferred Term		Mobilization Phase
(N = 166)

Musculoskeletal and connective tissue disorders

  Bone pain

30%

General disorders and administration site conditions

  Pyrexia

16%

Investigations

  Blood alkaline phosphatase increased

11%

Nervous system disorders

  Headache

10%

Adverse Reactions in Patients with Severe Chronic Neutropenia

The following adverse reaction data were identified in a randomized, controlled study in patients with SCN receiving filgrastim (Study 7). 123 patients were randomized to a 4-month observation period followed by subcutaneous filgrastim treatment or immediate subcutaneous filgrastim treatment. The median age was 12 years (range 7 months to 76 years) and 46% were male. The dosage of filgrastim was determined by the category of neutropenia. Initial dosage of filgrastim:

•
Idiopathic neutropenia: 3.6 mcg/kg/day
•
Cyclic neutropenia: 6 mcg/kg/day
•
Congenital neutropenia: 6 mcg/kg/day divided 2 times per day

The dosage was increased incrementally to 12 mcg/kg/day divided 2 times per day if there was no response.

Adverse reactions with ≥ 5% higher incidence in filgrastim patients compared to patients receiving no filgrastim included arthralgia, bone pain, back pain, muscle spasms, musculoskeletal pain, pain in extremity, splenomegaly, anemia, upper respiratory tract infection, and urinary tract infection (upper respiratory tract infection and urinary tract infection were higher in the filgrastim arm, total infection related events were lower in filgrastim-treated patients), epistaxis, chest pain, diarrhea, hypoesthesia, and alopecia.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of filgrastim 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 [see Warnings and Precautions (5.2)]
•
anaphylaxis [see Warnings and Precautions (5.3)]
•
sickle cell disorders [see Warnings and Precautions (5.4)]
•
glomerulonephritis [see Warnings and Precautions (5.5)]
•
alveolar hemorrhage and hemoptysis [see Warnings and Precautions (5.6)]
•
capillary leak syndrome [see Warnings and Precautions (5.7)]
•
leukocytosis [see Warnings and Precautions (5.10)]
•
cutaneous vasculitis [see Warnings and Precautions (5.11)]
•
Sweet's syndrome (acute febrile neutrophilic dermatosis)
•
decreased bone density and osteoporosis in pediatric patients receiving chronic treatment with filgrastim products.
•
myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with breast and lung cancer receiving chemotherapy and/or radiotherapy [see Warnings and Precautions (5.8)]
•
aortitis [see Warnings and Precautions (5.15)]
•
extramedullary hematopoiesis
Medication Guide

MEDICATION GUIDE

Patient Information
NIVESTYM (Neye-ves-tim)
(filgrastim-aafi)
injection

What is NIVESTYM?

NIVESTYM is a man-made form of granulocyte colony-stimulating factor (G-CSF). G-CSF is a substance produced by the body. It stimulates the growth of neutrophils, a type of white blood cell important in the body's fight against infection.

Do not take NIVESTYM if you have had a serious allergic reaction to human G-CSFs such as filgrastim products or pegfilgrastim products.

Before you take NIVESTYM, tell your healthcare provider about all of your medical conditions, including if you:

•
have a sickle cell disorder.
•
have kidney problems.
•
are receiving radiation therapy.
•
are pregnant or plan to become pregnant. It is not known if NIVESTYM will harm your unborn baby.
•
are breastfeeding or plan to breastfeed. It is not known if NIVESTYM passes into your breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How will I receive NIVESTYM?

•
NIVESTYM injections can be given by a healthcare provider by intravenous (IV) infusion or under your skin (subcutaneous injection). Your healthcare provider may decide subcutaneous injections can be given at home by you or your caregiver. If NIVESTYM is given at home, see the detailed "Instructions for Use" that comes with your NIVESTYM for information on how to prepare and inject a dose of NIVESTYM.
•
You and your caregiver should be shown how to prepare and inject NIVESTYM before you use it, by your healthcare provider.
•
You should not try to inject a dose of NIVESTYM less than 0.3 mL (180 mcg) from a NIVESTYM prefilled syringe. A dose less than 0.3 mL cannot be accurately measured using the NIVESTYM prefilled syringe.
•
Your healthcare provider will tell you how much NIVESTYM to inject and when to inject it. Do not change your dose or stop NIVESTYM unless your healthcare provider tells you to.
•
If you are receiving NIVESTYM because you are also receiving chemotherapy, your dose of NIVESTYM should be injected at least 24 hours before or 24 hours after your dose of chemotherapy. Your healthcare provider will do blood tests to monitor your white blood cell count, and if necessary, adjust your NIVESTYM dose.
•
If you miss a dose of NIVESTYM, talk to your healthcare provider about when you should give your next dose.

What are the possible side effects of NIVESTYM?

NIVESTYM may cause serious side effects, including:

•
Spleen rupture. Your spleen may become enlarged and can rupture. A ruptured spleen can cause death. Call your healthcare provider right away if you have pain in the left upper stomach (abdomen) area or your left shoulder.
•
A serious lung problem called acute respiratory distress syndrome (ARDS). Call your healthcare provider or get emergency medical help right away if you have shortness of breath with or without a fever, trouble breathing, or a fast rate of breathing.
•
Serious allergic reactions. NIVESTYM can cause serious allergic reactions. These reactions can cause a rash over your whole body, shortness of breath, wheezing, dizziness, swelling around your mouth or eyes, fast heart rate, and sweating. If you have any of these symptoms, stop using NIVESTYM and call your healthcare provider or get emergency medical help right away.
•
Sickle cell crises. You may have a serious sickle cell crisis, which could lead to death, if you have a sickle cell disorder and receive NIVESTYM. Call your healthcare provider right away if you have symptoms of sickle cell crisis such as pain or difficulty breathing.
•
Kidney injury (glomerulonephritis). NIVESTYM can cause kidney injury. Call your healthcare provider right away if you develop any of the following symptoms:
o
swelling of your face or ankles
o
blood in your urine or dark colored urine
o
you urinate less than usual
•
Capillary leak syndrome. NIVESTYM can cause fluid to leak from blood vessels into your body's tissues. This condition is called "Capillary Leak Syndrome" (CLS). CLS can quickly cause you to have symptoms that may become life-threatening. Get emergency medical help right away if you develop any of the following symptoms:
o
swelling or puffiness and are urinating less than usual
o
trouble breathing
o
swelling of your stomach area (abdomen) and feeling of fullness
o
dizziness or feeling faint
o
a general feeling of tiredness
•
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
o
NIVESTYM may increase the risk of developing a precancerous condition called MDS or a type of blood cancer called AML in people who were born with low white blood cell counts (congenital neutropenia).
o
If you have breast cancer or lung cancer, when NIVESTYM is used with chemotherapy and radiation therapy, or with radiation therapy only, you may have an increased risk of developing MDS or AML.
o
Symptoms of MDS and AML may include tiredness, fever, and easy bruising or bleeding.
o
Call your healthcare provider if you develop any of these symptoms during treatment with NIVESTYM.
•
Decreased platelet count (thrombocytopenia). Your healthcare provider will check your blood during treatment with NIVESTYM. Tell your healthcare provider if you have unusual bleeding or bruising during treatment with NIVESTYM. This could be a sign of decreased platelet counts, which may reduce the ability of your blood to clot.
•
Increased white blood cell count (leukocytosis). Your healthcare provider will check your blood during treatment with NIVESTYM.
•
Inflammation of your blood vessels (cutaneous vasculitis). Tell your healthcare provider right away if you develop purple spots or redness of your skin.
•
Inflammation of the aorta (aortitis). Inflammation of the aorta (the large blood vessel which transports blood from the heart to the body) has been reported in patients who received NIVESTYM. Symptoms may include fever, abdominal pain, feeling tired, and back pain. Call your healthcare provider if you experience these symptoms.

The most common side effects experienced in patients receiving NIVESTYM include:

•
Patients with cancer receiving chemotherapy: fever, pain, rash, cough, and shortness of breath
•
Patients with acute myeloid leukemia receiving chemotherapy: pain, nose bleed, and rash
•
Patients with cancer receiving chemotherapy followed by bone marrow transplant: rash
•
Patients who are having their own blood cells collected: bone pain, fever, and headache
•
Patients with severe chronic neutropenia: pain, decreased red blood cells, nose bleed, diarrhea, reduced sensation, and hair loss

These are not all the possible side effects of NIVESTYM. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store NIVESTYM?

•
Store NIVESTYM in the refrigerator between 36°F to 46°F (2°C to 8°C).
•
Do not freeze.
•
Keep NIVESTYM in the original carton to protect from light or physical damage. Do not leave NIVESTYM in direct sunlight.
•
Do not shake NIVESTYM.
•
Take NIVESTYM out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection.
•
Throw away (dispose of) any NIVESTYM that has been left at room temperature for longer than 24 hours.
•
After you inject your dose, throw away (dispose of) any unused NIVESTYM left in the vials or prefilled syringes. Do not save unused NIVESTYM in the vials or prefilled syringes for later use.

Keep NIVESTYM out of the reach of children.

General information about the safe and effective use of NIVESTYM.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use NIVESTYM for a condition for which it was not prescribed. Do not give NIVESTYM to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about NIVESTYM that is written for healthcare professionals.

What are the ingredients in NIVESTYM?

Active ingredient: (filgrastim-aafi)

Inactive ingredients: acetate, polysorbate 80, sodium, sorbitol, and water for Injection

Manufactured by Hospira, Inc., a Pfizer Company, Lake Forest, IL 60045 USA
US License No. 1974

Distributed by Pfizer Labs, division of Pfizer Inc., New York, NY 10001 USA

LAB-0935-5.0
For more information go to www.pfizer.com or call 1-800-438-1985.

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This Patient Information has been approved by the U.S. Food and Drug Administration     Revised: March 2023

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