Filgrastim

Filgrastim is a man-made protein that is similar to the naturally occurring protein, granulocyte-colony stimulating factor (G-CSF). G-CSF is produced in the body by the immune system and stimulates the formation of one type of white blood cell, the neutrophil. Neutrophils take part in the inflammatory reaction. They are responsible for detecting and destroying harmful bacteria and some fungi. Filgrastim is produced by bacteria through the use of genetic engineering and recombinant DNA technology. Filgrastim belongs to a class of drugs called colony-stimulating factors because of their ability to stimulate cells in the bone marrow to multiply and form colonies of new cells. Other CSFs include epoetin alfa (Epogen, Procrit) which stimulates the formation of red blood cells and sargramostim (Leukine) which also stimulates the formation of neutrophils. The FDA approved filgrastim in February 1991.

There are no studies to determine if filgrastim is excreted into breast milk.

Filgrastim is a prescription medication used to prevent infections in people getting chemotherapy or bone marrow transplants, or in people who have low neutrophil counts caused by other conditions. It is also used to prepare blood for stem cell collection.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Serious side effects can occur with filgrastim use. See "Filgrastim 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 filgrastim, 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.

Other drugs may interact with filgrastim, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Filgrastim, filgrastim-sndz, and tbo-filgrastim are granulocyte colony stimulating factors (G-CSF) produced by recombinant DNA technology. G-CSFs stimulate the production, maturation, and activation of neutrophils to increase both their migration and cytotoxicity.

Distribution

Vd: 150 mL/kg; Continuous infusion: No evidence of drug accumulation over a 11- to 20-day period

Metabolism

Systemically degraded

History of serious allergic reactions to human granulocyte colony-stimulating factors, such as filgrastim or pegfilgrastim, or any component of the formulation

Canadian labeling: Additional contraindications (not in the US labeling): Neupogen, Grastofil: Known hypersensitivity to E. coli-derived products

Neupogen, Zarxio: No dosage adjustment necessary.

Granix: There are no dosage adjustments provided in the manufacturer′s labeling (has not been studied).

Some products may contain sodium.

Commonly reported side effects of filgrastim include: hyperuricemia, increased lactate dehydrogenase, increased leukocyte alkaline phosphatase, increased serum alkaline phosphatase, ostealgia, and thrombocytopenia. Other side effects include: arthralgia, headache, myalgia, and pruritus. See below for a comprehensive list of adverse effects.

Applies to filgrastim: injection injectable, injection solution

Along with its needed effects, filgrastim may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking filgrastim:

• Abdominal or stomach pain
• bleeding gums
• bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site
• blood in the urine or stools
• bloody nose
• cough
• coughing up blood
• diarrhea
• difficult or labored breathing
• difficulty with swallowing
• dizziness
• facial swelling
• feeling of fullness
• fever or chills
• headache
• increased menstrual flow or vaginal bleeding
• lower back or side pain
• nausea or vomiting
• nosebleeds
• pain in the back, ribs, arms, or legs
• pain spreading to the left shoulder
• painful or difficult urination
• pale skin
• paralysis
• pinpoint red or purple spots on the skin
• prolonged bleeding from cuts
• red or black, tarry stools
• red or dark brown urine
• skin rash
• sore throat
• sores, ulcers, or white spots on the lips, tongue, or inside the mouth
• tightness in the chest
• troubled breathing with exertion
• unusual bleeding or bruising
• unusual tiredness or weakness

• Blurred vision
• chest pain
• nervousness
• pounding in the ears
• slow or fast heartbeats

• Blisters on the skin
• blue lips, fingernails, or skin
• difficult or fast breathing
• sores on the skin

Some side effects of filgrastim may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Bone, joint, or muscle pain
• hair loss or thinning of the hair
• loss of appetite
• weight loss

• Cracked lips
• difficulty having a bowel movement (stool)
• swelling or inflammation of the mouth

No adjustment recommended.

This drug should be used during pregnancy only if the benefit outweighs the risk. AU TGA pregnancy category: B3 US FDA pregnancy category: C

In animal studies at doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred. Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies or reproductive/developmental toxicity observed at doses 10 times the recommended human dose (based on body surface area). There are no controlled data in human pregnancy. It is not known whether this drug can cause fetal harm or adversely affect reproductive capacity in humans. AU TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Summary of Use during Lactation

Granulocyte colony-stimulating factor (G-CSF) is a normal component of breastmilk. However, the excretion of exogenous filgrastim in breastmilk or its effects on breastfed infants have not been well studied. Limited data indicate that filgrastim and a similar G-CSF product, lenograstim, are poorly excreted into breastmilk and are undetectable by 3 days after an injection. Some authors recommend withholding breastfeeding for this period of time.[1] However, filgrastim has been safely given orally to neonates and is not orally absorbed by neonates, so any filgrastim that is excreted into milk is unlikely to adversely affect the breastfed infant.

Drug Levels

Granulocyte colony-stimulating factor (G-CSF) is a normal component of breastmilk. In the United States, the biosynthetic form that is available for exogenous administration is filgrastim. Other biosynthetic forms of G-CSF are available in other countries. Lenograstim is a glycosylated recombinant G-CSF whereas filgrastim is not glycosylated.

Maternal Levels. A nursing mother who was 4 months postpartum was given the recombinant G-CSF product lenograstim in order to donate peripheral blood stem cells. She was given lenograstim subcutaneously in doses of 300 mcg on day 1,600 mcg daily on days 2 to 4 and 300 mcg daily on days 5 and 6 of therapy. G-CSF concentration in milk was less than 5 ng/L before therapy. G-CSF milk levels increased during therapy with levels of about 58 ng/L on day 4, 78 ng/L on day 5, and 85.7 ng/L on day 6. Sampling times were not stated.[2] The maximum amount in milk represents an infant dosage of about 0.013 mcg/kg which is 13% of an infant subcutaneous dose of exogenous G-CSF and 0.13% of the maternal weight-adjusted dosage.

A woman received subcutaneous injections of filgrastim in the following doses: 600 mcg on day 1,300 mcg twice daily on days 2 to 5, and 300 mcg once on day 6 prior to harvesting white cells for donation. She was nursing her 25-day-old infant and milk G-CSF levels were measured once daily just before the first dose of the day. G-CSF was first detectable (>10 ng/L) in whole milk 12 hours after the start of the regimen, had a peak milk concentration of 188 ng/L at 22 hours after the start of the regimen, and then after 43 hours, slowly declined until G-CSF was undetectable (<10 ng/L) in breastmilk 70 hours after the last dose.[3]

Infant Levels. Published information on absorption of filgrastim from breastmilk was not found as of the revision date. However, a study in which an oral dose of 100 mcg/kg of filgrastim (10 times the subcutaneous dose) was given to preterm infants found that filgrastim was not absorbed.[4]

Effects in Breastfed Infants

Published information on the effects of filgrastim in breastmilk was not found as of the revision date. However, oral filgrastim 20 mcg daily for 5 days has been given to preterm infants with stage I necrotizing enterocolitis (NEC). Filgrastim appeared to halt progression to more severe stages of NEC in this small study.[5]

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

References

1. Pessach I, Shimoni A, Nagler A. Granulocyte-colony stimulating factor for hematopoietic stem cell donation from healthy female donors during pregnancy and lactation: what do we know? Hum Reprod Update. 2013;19:259-67. PMID: 23287427

2. Shibata H, Yamane T, Aoyama Y et al. Excretion of granulocyte colony-stimulating factor into human breast milk. Acta Haematol. 2003;110:200-1. PMID: 14663166

3. Kaida K, Ikegame K, Fujioka T et al. Kinetics of granulocyte colony-stimulating factor in the human milk of a nursing donor receiving treatment for mobilization of the peripheral blood stem cells. Acta Haematol. 2007;118:176-7. PMID: 17914246

4. Calhoun DA, Maheshwari A, Christensen RD. Recombinant granulocyte colony-stimulating factor administered enterally to neonates is not absorbed. Pediatrics. 2003;112:421-3. PMID: 12897302

5. Canpolat FE, Yurdakok M, Korkmaz A et al. Enteral granulocyte colony-stimulating factor for the treatment of mild (stage I) necrotizing enterocolitis: a placebo-controlled pilot study. J Pediatr Surg. 2006;41:1134-8. PMID: 16769348

Substance Name

Filgrastim

CAS Registry Number

121181-53-1

Drug Class

Colony-Stimulating Factors

Hematopoietic Cell Growth Factors