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pegfilgrastim

Trade Name:

Neulasta®

Lapelga™

Fulphila™

Ziextenzo®

Nyvepria™

Appearance:

Clear, colourless solution for injection in a pre-filled syringe

Monograph Name:

pegfilgrastim

Monograph Body:

Drug Monograph

A - Drug Name

pegfilgrastim

COMMON TRADE NAME(S): Neulasta®; Lapelga™; Fulphila™; Ziextenzo®; Nyvepria™

Different pegfilgrastim products are not interchangeable.
For additional information on biosimilars, refer to:
- Position Statements for the Clinical Operational Implementation of Oncology Biosimilars from the pan-Canadian Clinical Operations Working Group
- Clinician Fact Sheet

B - Mechanism of Action and Pharmacokinetics

Pegfilgrastim is a long-acting form of filgrastim, composed of filgrastim (recombinant human granulocyte colony-stimulating factor or G-CSF) covalently bonded to polyethylene glycol (PEG). Like filgrastim, pegfilgrastim regulates the production of neutrophils within the bone marrow and affects neutrophil progenitor proliferation‚ differentiation, and selected end-cell functions. Conjugation with PEG results in reduced renal clearance and prolonged duration of effect compared to filgrastim.

Absorption

The absorption of pegfilgrastim is largely dependent on the lymphatic system due to the attached PEG group contributing to the large size of the drug. It is slowly absorbed following subcutaneous administration.

Bioavailability

60-70% (subcut)

T max

~ 1-2 days (subcut)

Distribution

Cross blood brain barrier?

unknown

PPB

unlikely

Metabolism

It is not known if pegfilgrastim is metabolized. Once it binds to the therapeutic target, pegfilgrastim is internalized by the neutrophil and undergoes nonspecific degradation.

Elimination

Pegfilgrastim has a self-regulating clearance and is mainly eliminated via a saturable neutrophil-mediated route. The clearance is dependent on the number of neutrophils and body weight of the patient: The clearance increases with increasing number of neutrophils and lower body weights.

Urine

minimal

Half-life

25-49 hours (after subcut use)

C - Indications and Status

Health Canada Approvals:

Decrease the incidence of infection (i.e. febrile neutropenia) in patients with non-myeloid malignancies receiving myelosuppressive antineoplastic drugs.

D - Adverse Effects

The following table contains adverse effects reported in patients with lymphoma and solid tumours (breast and thoracic) treated with pegfilgrastim following non-myeloablative chemotherapy, where the incidence was higher than placebo. It also includes severe, life-threatening and post-marketing adverse effects.

ORGAN SITE	SIDE EFFECT* (%)	ONSET**
Cardiovascular	Other - aortitis (rare)	E
Dermatological	Cutaneous vasculitis (rare)	E
	Other (Sweet's syndrome; rare)	E
Hematological	Leukocytosis (> 100 x 10^9/L: <1%)	E
	Sickle cell crisis (in patients with sickle cell trait or disease; rare)	E
	Splenic rupture (+/- splenomegaly; rare)	E
	Thrombocytopenia (rare, may be severe)	E
Hypersensitivity	Hypersensitivity (rare)	I
Injection site	Injection site reaction (<1%)	I
Musculoskeletal	Musculoskeletal pain (13%)	E
Neoplastic	Leukemia (secondary) (rare)	D
Nervous System	Headache (1%)	E
	Other - hypertonia (<1%)	E
Ophthalmic	Other - periorbital edema (<1%)	E
Renal	Nephritis (glomerulonephritis) (rare)	E
Respiratory	Acute respiratory distress syndrome (ARDS) (rare)	E
Vascular	Capillary leak syndrome (rare)	E

* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)

Across all studies, no life-threatening or fatal adverse events were attributed to pegfilgrastim and most adverse experiences were attributed as the sequelae of the underlying malignancy or cytotoxic chemotherapy. The most common adverse effects are bone pain and muscle pain. Bone pain was generally reported as mild-to-moderate, and could be controlled with non-narcotic analgesics in most patients.

Marked leukocytosis (>100 x 10⁹ /L) has occurred occasionally. However, there were no reports of adverse clinical effects associated with this degree of leukocytosis.

Aortitis has been reported in patients receiving pegfilgrastim. It may occur as early as the first week after start of therapy. Manifestations may include generalized signs and symptoms such as fever, abdominal pain, malaise, back pain, and increased inflammatory markers (e.g., c-reactive protein and white blood cell).

Hypersensitivity reactions, including anaphylaxis, skin rash, urticaria have been described; these may occur on initial, subsequent, or re-challenge treatments. In rare cases, allergic reactions (including anaphylactic reactions) can recur within days after the discontinuation of initial anti-allergic treatment.

Cases of glomerulonephritis have been reported in patients receiving pegfilgrastim, usually resolving after dose reductions or withdrawal.

Rare splenic rupture, including fatal cases, have been reported following pegfilgrastim administration. Patients who report left upper abdominal or shoulder tip pain following pegfilgrastim use should be investigated for an enlarged spleen or splenic rupture.

Acute respiratory distress syndrome (ARDS) have occurred with pegfilgrastim use, possibly due to the influx of neutrophils to the inflammation sites on the lungs.

Capillary leak syndrome (CLS), characterized by hypotension, hypoalbuminemia, edema, and hemoconcentration, has been reported and may be life-threatening. Prompt treatment is required.

An increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) has been associated with pegfilgrastim when used in conjunction with chemotherapy and/or radiotherapy in patients with breast and lung cancer.

There have been reports of patients developing binding, but not neutralizing, antibodies to pegfilgrastim.

E - Dosing

Refer to protocol by which patient is being treated.

Different pegfilgrastim products are not interchangeable.

Adults:

6 mg Subcut as a single dose given 24 to 72 hours post systemic treatment (once per cycle).
Pegfilgrastim can be given with regimens that are administered every 14 days or more. There must be an interval of at least 12 days from the time of pegfilgrastim to the next dose of myelosuppressive systemic treatment; however, there may be exceptions depending on the treatment regimen and clinical trial protocol.

Also refer to the Clinical Practice Guideline - Prevention and Outpatient Management of Febrile Neutropenia in Adult Cancer Patients.

Dosage with Toxicity:

Toxicity	Pegfilgrastim Dose
Severe hypersensitivity or anaphylactic reaction	Discontinue
Capillary leak syndrome
ARDS
Aortitis
Sickle cell crisis
Alveolar hemorrhage	Hold until resolution or discontinue
Glomerulonephritis	Consider dose reduction or discontinue

May consider filgrastim for patients who experience severe musculoskeletal pain.

Dosage with Hepatic Impairment:

No information found. Changes in pegfilgrastim pharmacokinetics are not expected as the drug is mainly eliminated via neutrophil-mediated clearance.

Dosage with Renal Impairment:

No dose adjustment required in end-stage renal disease or renal impairment.

Dosage in the elderly:

No dose adjustment required. There were no overall differences in safety or effectiveness observed in pegfilgrastim treated patients ≥ 65 years of age compared to younger patients.

Children:

The safety and effectiveness of pegfilgrastim in pediatric patients have not been established.

F - Administration Guidelines

Different pegfilgrastim products are not interchangeable.

Available as a prefilled syringe for subcutaneous use only. Do not shake drug.
Do not mix with any diluents.
The pre-filled syringes for some pegfilgrastim products contain a derivative of latex which may cause allergic reactions in some people. Refer to the product monograph. These products should not be handled by individuals sensitive to latex.
If a scheduled dose is missed and there is less than 12 days before the next dose of systemic treatment, the pegfilgrastim dose should not be given.
Keep refrigerated; do not freeze. Protect from light.
Refer to the respective product monograph(s) for stability information at room temperature before injection.

G - Special Precautions

Contraindications:

Patients with known hypersensitivity to E. coli derived proteins, pegfilgrastim, filgrastim or any other components of the product

Other Warnings/Precautions:

Pegfilgrastim has not been evaluated in use for peripheral blood progenitor cell mobilization and should not be used in that setting. The use of pegfilgrastim in chronic myeloid leukemia (CML) and MDS has not been studied.
Since some cell lines (i.e. head and neck, lung, myeloid, T-lymphoid, bladder) express the G-CSF receptor, the possibility of pegfilgrastim acting as a tumour growth factor cannot be excluded.
Since patients are more likely to receive full dose chemotherapy with pegfilgrastim support, they may be at greater risk of thrombocytopenia, anemia and non-hematologic adverse effects of chemotherapy. Exercise caution when pegfilgrastim is administered with drugs that can lower platelet count.
Patients with sickle cell disease (may precipitate sickle cell crisis).

Other Drug Properties:

Carcinogenicity: Unlikely

Pregnancy and Lactation:

Mutagenicity: No
Embryotoxicity: Probable
Pegfilgrastim should only be used during pregnancy if the potential benefit outweighs the risk to the fetus.
Crosses placental barrier: Documented in animals
Excretion into breast milk: Unknown

Breastfeeding is not recommended.
Fertility effects: Unlikely

H - Interactions

AGENT	EFFECT	MECHANISM	MANAGEMENT
Lithium	Greater than expected increase in neutrophils	Potentiate release of neutrophils	Use with caution; more frequent monitoring of neutrophil counts
Bone imaging	Transient positive bone imaging changes	↑ hematopoietic activity in the bone marrow	Consider when interpreting bone imaging results
cytotoxics	↑ myelosuppression	↑ sensitivity of myeloid cells	Do not administer pegfilgrastim within 12 days before or within 24 hours after cytotoxics
antineoplastics with delayed myelosuppression (e.g. nitrosourea derivatives) or mitomycin or myelosuppressive doses of antimetabolites	additive myeloproliferative effect	theoretically antagonist mechanism	Caution (unknown significance)

I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type	Monitor Frequency
CBC	Baseline, before chemotherapy, and as clinically indicated
Urinalysis	Baseline and as clinically indicated
Clinical assessment for bone pain, upper abdominal pain, hypersensitivity, pulmonary and dermatological effects, aortitis	At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

J - Supplementary Public Funding

ODB - General Benefit (ODB Formulary )

pegfilgrastim - Lapelga brand
pegfilgrastim - Fulphila brand
pegfilgrastim - Ziextenzo brand
pegfilgrastim - Nyvepria brand

K - References

Clinical Practice Guideline - Prevention and Outpatient Management of Febrile Neutropenia in Adult Cancer Patients. Ontario Health (Cancer Care Ontario), 2021.

Filgrastim drug monograph, Ontario Health (Cancer Care Ontario) 2021.

Pegfilgrastim in AHFS Drug Information 2009. American Society of Health-System Pharmacists, 2009.

Pegfilgrastim, from Micromedex: Drugdex®. Zamboni WC. Pharmacokinetics of pegfilgrastim. Pharmacotherapy 2003;23(8 Pt 2):9S–14S.

Prescribing Information: Neulasta® (pegfilgrastim). Amgen Inc. U.S. January 2021.

Product Monograph: Neulasta® (pegfilgrastim). Amgen Canada, January 8, 2021.

Yang BB, Kido A. Pharmacokinetics and pharmacodynamics of pegfilgrastim. Clin Pharmacokinet. 2011;50(5):295-306. doi:10.2165/11586040-000000000-00000.

Zamboni WC. Pharmacokinetics of pegfilgrastim. Pharmacotherapy 2003;23(8 Pt 2):9S–14S.

August 2022 Updated Mechanism of Action and Pharmacokinetics, Adverse Effects, and Dosage with Toxicity sections

L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.

Info Sheet Name:

pegfilgrastim (patient)

Info Sheet Introduction:

Pegfilgrastim is used to increase the growth of your white blood cells, which help your body fight against infection.
Pegfilgrastim is available as a biosimilar medication. See our biosimilar pamphlet for more information.

Info Sheet Date: Wednesday, December 7, 2022 Info Sheet body:

Medication Information Sheet

pegfilgrastim (peg-fill-GRA-stim)

This document provides general information about your medication. It does not replace the advice of your health care professional. Always discuss your therapy with your health care professional and refer to the package insert for more details.

Other Name: Neulasta®, Lapelga™, Fulphila™, Nyvepria™

Appearance:

Clear, colourless solution for injection in a pre-filled syringe

What is this medication for?

Pegfilgrastim is used to increase the growth of your white blood cells, which help your body fight against infection.
Pegfilgrastim is available as a biosimilar medication. See our biosimilar pamphlet for more information.

What should I do before I have this medication?

Tell your health care team if you have or had significant medical condition(s), especially if you have / had:

heart disease,
sickle cell anemia, or
any allergies

Remember to:

Tell your health care team about all of the other medications you are taking.
Keep taking other medications that have been prescribed for you, unless you have been told not to by your health care team.

How will this medication affect sex, pregnancy and breastfeeding?

Talk to your health care team about:

How this medication may affect your sexual health.
How this medication may affect your ability to have a baby, if this applies to you.

This medication has not been studied in pregnant women, and its effects on unborn babies are not known. Tell your health care team if you or your partner are pregnant, become pregnant during treatment, or are breastfeeding.

If there is any chance of pregnancy happening, you and your partner should speak with your health care team before using this medication.

Do not breastfeed while on this medication.

How is this medication given?

This medication is usually given as an injection under the skin, once per chemotherapy cycle. Talk to your health care team about your treatment schedule.
If you (or your caregiver) are giving the injection, your health care team will teach you (or your caregiver) how to give the injection. Be sure you understand the proper method for preparing and injecting the drug. Talk to your nurse or pharmacist for more information.
You must wait at least 24 hours after your course of chemotherapy before injecting pegfilgrastim.
There should be at least 12 days between your pegfilgrastim dose and your next chemotherapy.
You may take the medication out of the refrigerator about 30 minutes before using it, so that the injection is more comfortable.
If you miss your pegfilgrastrm dose, talk to your health care team to find out what to do.
If you take too much of your medication by accident, or if you think a child or a pet may have swallowed your medication, you must call the Ontario Poison Control Center right away at: 1-800-268-9017.

What else do I need to know while on this medication?

Will this medication interact with other medications or natural health products?

This medication can interact with other medications, vitamins, foods and natural health products. Interactions can make the treatment not work as well or cause severe side effects.
Tell your health care team about all of your:
- prescription and over-the-counter (non-prescription) medications and all other drugs, such as cannabis/marijuana (medical or recreational)
- natural health products such as vitamins, herbal teas, homeopathic medicines, and other supplements
Check with your health care team before starting or stopping any of them.

What to DO while on this medication:

DO check with your health care team before getting any vaccinations, surgery, dental work or other medical procedures.
DO talk to your health care team about your risk of getting other cancers after this treatment.
DO tell your health care team about any signs of infection.

What NOT to DO while on this medication:

DO NOT smoke or drink alcohol while on treatment without talking to your health care team first. Smoking and drinking can make side effects worse and make your treatment not work as well.

How should I safely store this medication?

Keep in the refrigerator, but do not freeze. Keep out of sight and reach of children and pets.
Keep in the carton to protect it from light until ready to use.
Used needle covers, needles and syringes should never be reused and must always be disposed of in a puncture-proof or “sharps” container given to you by your pharmacist.
Ask your pharmacist for help to properly dispose of these items, including the filled container.
Do not throw out any unused medications at home. Bring them to your pharmacy to be thrown away safely.

What are the side effects of this medication?

The following table lists side effects that you may have when getting pegfilgrastim. The table is set up to list the most common side effects first and the least common last. It is unlikely that you will have all of the side effects listed and you may have some that are not listed.

Read over the side effect table so that you know what to look for and when to get help. Refer to this table if you experience any side effects while on filgrastim.

If you develop signs or symptoms of an infection (if your temperature taken in your mouth (oral temperature) is above 38.3°C or 100.9°F at any time OR above 38.0°C or 100.4°F for at least one hour, chills, sore throat), call your doctor and get emergency medical help right away.

Less Common Side Effects (10 to 24 out of 100 people)
Mild joint, muscle, back or bone pain What to look for? New pain in your muscles, joints or bones. What to do? Rest often and try light exercise (such as walking) as it may help. Take pain medication (acetaminophen or opioids such as codeine, morphine, hydromorphone, oxycodone) as prescribed. Always check your temperature to see if you have a fever before taking acetaminophen (Tylenol®), ibuprofen (Advil®, Motrin®), naproxen (Aleve®) or aspirin. Fever can be a sign of infection that may need treatment right away. If you take these medications before you check for fever, they may lower your temperature and you may not know you have an infection. How to check for fever: Keep a digital (electronic) thermometer at home and take your temperature if you feel hot or unwell (for example, chills, headache, mild pain). You have a fever if your temperature taken in your mouth (oral temperature) is: 38.3°C (100.9°F) or higher at any time OR 38.0°C (100.4°F) or higher for at least one hour. Ask your health care team for the Pain pamphlet for more information.	Talk to your health care team if it does not improve or if it is severe.

Less Common Side Effects (10 to 24 out of 100 people)

Side effects and what to do

When to contact health care team

Mild joint, muscle, back or bone pain

What to look for?

New pain in your muscles, joints or bones.

What to do?

Rest often and try light exercise (such as walking) as it may help.
Take pain medication (acetaminophen or opioids such as codeine, morphine, hydromorphone, oxycodone) as prescribed.
Always check your temperature to see if you have a fever before taking acetaminophen (Tylenol®), ibuprofen (Advil®, Motrin®), naproxen (Aleve®) or aspirin.
- Fever can be a sign of infection that may need treatment right away.
- If you take these medications before you check for fever, they may lower your temperature and you may not know you have an infection.

How to check for fever:

Keep a digital (electronic) thermometer at home and take your temperature if you feel hot or unwell (for example, chills, headache, mild pain).

You have a fever if your temperature taken in your mouth (oral temperature) is:
- 38.3°C (100.9°F) or higher at any time
  OR
- 38.0°C (100.4°F) or higher for at least one hour.

Ask your health care team for the Pain pamphlet for more information.

Talk to your health care team if it does not improve or if it is severe.

Other rare, but serious side effects are possible.
If you experience ANY of the following, speak to your cancer health care provider or get emergency medical help right away:

shortness of breath, cough or coughing up blood
swelling or puffiness, sudden weight gain, difficulty breathing, fainting, severe bloating in the belly and feeling of fullness, or feeling very tired
rash on the skin that looks like purple or red spots or bumps, clusters of small dots, splotches or hives. It may also be itchy.
fever, painful, red rash that grows quickly in size
rash, chest or throat tightness during or shortly after the drug is given
reactions at the injection site such as redness, swelling, itching or bruising
swollen ankles, blood in urine (pee) or brown coloured urine, or passing little or no urine
pain in the left upper belly or shoulder
severe chest, belly or joint pain
unusual bruising or bleeding (such as nose bleeds or bleeding from the gums, black coloured stools (poo) or blood in your stools (poo)

Who do I contact if I have questions or need help?

My cancer health care provider is: ______________________________________________

During the day I should contact:________________________________________________

Evenings, weekends and holidays:______________________________________________

Other Notes:

____________________________________________________________________________

August 2022 Updated/Revised info sheet

For more links on how to manage your symptoms go to www.cancercareontario.ca/symptoms.

The information set out in the medication information sheets, regimen information sheets, and symptom management information (for patients) contained in the Drug Formulary (the "Formulary") is intended to be used by health professionals and patients for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or side effects of a certain drug, nor should it be used to indicate that use of a particular drug is safe, appropriate or effective for a given condition.

A patient should always consult a healthcare provider if he/she has any questions regarding the information set out in the Formulary. The information in the Formulary is not intended to act as or replace medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

Info Sheet (English):

pegfilgrastim patient.pdf Info Sheet (French):

pegfilgrastim pour le patient.pdf Monograph:

pegfilgrastim.pdf Funding Program: ODB - General Benefit Funding Instance:

pegfilgrastim - Lapelga brand
pegfilgrastim - Fulphila brand
pegfilgrastim - Ziextenzo brand
pegfilgrastim - Nyvepria brand

Phonetic Spelling:

peg-fill-GRA-stim

Cancer Type: Genitourinary Renal cell / Kidney Type of Content: Drug Monograph Status: Null Info Sheet Status: Null Global Date: Tuesday, August 23, 2022 Universal Date: 2022-12-07 00:00:00 AddThis: Title URL: pegfilgrastim Drug Display Status: Active Revision Summary:
Patient Info Sheet FR: Updated/revised info sheet (Fiche d’information mise à jour/révisée)