Leukine

The most common side effects while taking sargramostim are:

• stomach pain,
• mild to moderate fever,
• weakness,
• chills,
• headache,
• nausea,
• vomiting,
• diarrhea,
• rash,
• muscle and bone pain.
• shortness of breath,
• weight loss,
• leg and arm swelling,
• injection site reactions,
• serious allergic reactions and
• abnormal heart beats.

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

• Genzyme Corporation

Serious side effects have been reported with Leukine. See the “Leukine Precautions” section.

The most common side effect during Leukine therapy is:

• mild bone pain, usually in the lower back or pelvis and lasting only a few days.
• flu-like syndrome with fever, fatigue, chills, and muscle aches. Your doctor may recommend that you take acetaminophen or other painkillers.
• feeling tired or weak
• muscle aches
• diarrhea
• stomach upset
• low fever (less than 100.5° F or 38° C) about one to four hours after an injection
• swelling, redness, and/or discomfort where Leukine is injected. Occasionally a skin reaction may occur at the injection site. This usually will not require you to stop taking Leukine. The skin may become red, painful, or swollen. If a skin reaction occurs, contact your doctor. 

This is not a complete list of Leukine side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Drug Interactions between Leukine and other drugs have not been fully evaluated. Drugs which may potentiate the myeloproliferative effects of Leukine, such as lithium and corticosteroids, should be used with caution.

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Leukine, there are no specific foods that you must exclude from your diet when receiving this medication.

If you take too much Leukine, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

Since Leukine is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Sargramostim is a man-made form of a protein that stimulates the growth of white blood cells in your body. White blood cells help your body fight against infection.

Sargramostim is used to help prevent serious infection in conditions such as leukemia, bone marrow transplant, and pre-chemotherapy blood cell collection. Sargramostim is for use in adults who are at least 55 years old.

Sargramostim may also be used for purposes not listed in this medication guide.

In the U.S.

• Leukine

Available Dosage Forms:

• Powder for Solution
• Solution

Therapeutic Class: Hematopoietic

Pharmacologic Class: Colony Stimulating Factor

Sargramostim is a synthetic (man-made) version of a substance that is naturally produced in your body called a colony stimulating factor. It helps the bone marrow to make new white blood cells .

When certain cancer medicines are used to fight cancer cells, they also affect the white blood cells that fight infections. Sargramostim is used to prevent or reduce the risk of infection while you are being treated with cancer medicines. This medicine is also used to help the bone marrow recover after a bone marrow transplantation, and for a process called peripheral blood progenitor cell collection in cancer patients .

This medicine is available only with your doctor's prescription .

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of sargramostim in children. However, safety and efficacy have not been established in babies younger than 4months of age .

Geriatric

Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of sargramostim in the elderly .

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Vincristine
• Vincristine Sulfate Liposome

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Bone marrow hyperplasia—Should not be used. Will result to higher risk of serious side effect in patients with this condition .

• Congestive heart failure or
• Edema (fluid retention) or
• Heart disease or
• Heart rhythm problems, history of or
• Hypoxia (decreased oxygen in the tissues) or
• Kidney disease or
• Liver disease or
• Lung disease or breathing problems or
• Pericardial effusion (fluid around the heart) or
• Pleural effusion (fluid around the lungs)—Use with caution. May make these conditions worse .

A nurse or other trained health professional may give you this medicine. Your doctor will prescribe your exact dose and tell you how often it should be given. This medicine is given through a needle placed in one of your veins .

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

General

GM-CSF belongs to a group of growth factors termed colony stimulating factors which support survival, clonal expansion, and differentiation of hematopoietic progenitor cells. GM-CSF induces partially committed progenitor cells to divide and differentiate in the granulocyte-macrophage pathways which include neutrophils, monocytes/macrophages and myeloid-derived dendritic cells.

GM-CSF is also capable of activating mature granulocytes and macrophages. GM-CSF is a multilineage factor and, in addition to dose-dependent effects on the myelomonocytic lineage, can promote the proliferation of megakaryocytic and erythroid progenitors.1 However, other factors are required to induce complete maturation in these two lineages. The various cellular responses (i.e., division, maturation, activation) are induced through GM-CSF binding to specific receptors expressed on the cell surface of target cells.2

In vitro Studies of Leukine in Human Cells

The biological activity of GM-CSF is species-specific. Consequently, in vitro studies have been performed on human cells to characterize the pharmacological activity of Leukine. In vitro exposure of human bone marrow cells to Leukine at concentrations ranging from 1–100 ng/mL results in the proliferation of hematopoietic progenitors and in the formation of pure granulocyte, pure macrophage and mixed granulocytemacrophage colonies.3 Chemotactic, anti-fungal and anti-parasitic4 activities of granulocytes and monocytes are increased by exposure to Leukine in vitro. Leukine increases the cytotoxicity of monocytes toward certain neoplastic cell lines3 and activates polymorphonuclear neutrophils to inhibit the growth of tumor cells.

In vivo Primate Studies of Leukine

Pharmacology/toxicology studies of Leukine were performed in cynomolgus monkeys. An acute toxicity study revealed an absence of treatment-related toxicity following a single IV bolus injection at a dose of 300 mcg/kg. Two subacute studies were performed using IV injection (maximum dose 200 mcg/kg/day × 14 days) and subcutaneous injection (SC) (maximum dose 200 mcg/kg/day × 28 days). No major visceral organ toxicity was documented. Notable histopathology findings included increased cellularity in hematologic organs and heart and lung tissues. A dose-dependent increase in leukocyte count, which consisted primarily of segmented neutrophils, occurred during the dosing period; increases in monocytes, basophils, eosinophils and lymphocytes were also noted. Leukocyte counts decreased to pretreatment values over a 1–2 week recovery period.

Pharmacokinetics

Pharmacokinetic profiles have been analyzed in controlled studies of 24 normal male volunteers. Liquid and lyophilized Leukine, at the recommended dose of 250 mcg/m2, have been determined to be bioequivalent based on the statistical evaluation of AUC.5

When Leukine (either liquid or lyophilized) was administered IV over two hours to normal volunteers, the mean beta half-life was approximately 60 minutes. Peak concentrations of GM-CSF were observed in blood samples obtained during or immediately after completion of Leukine infusion. For liquid Leukine, the mean maximum concentration (Cmax) was 5.0 ng/mL, the mean clearance rate was approximately 420 mL/min/m2 and the mean AUC (0–inf) was 640 ng/mL•min. Corresponding results for lyophilized Leukine in the same subjects were mean Cmax of 5.4 ng/mL, mean clearance rate of 431 mL/min/m2, and mean AUC (0–inf) of 677 ng/mL•min. GM-CSF was last detected in blood samples obtained at three or six hours.

When Leukine (either liquid or lyophilized) was administered SC to normal volunteers, GM-CSF was detected in the serum at 15 minutes, the first sample point. The mean beta half-life was approximately 162 minutes. Peak levels occurred at one to three hours post injection, and Leukine remained detectable for up to six hours after injection. The mean Cmax was 1.5 ng/mL. For liquid Leukine, the mean clearance was 549 mL/min/m2 and the mean AUC (0–inf) was 549 ng/mL•min. For lyophilized Leukine, the mean clearance was 529 mL/min/m2 and the mean AUC (0–inf) was 501 ng/mL•min.

General

Parenteral administration of recombinant proteins should be attended by appropriate precautions in case an allergic or untoward reaction occurs. Serious allergic or anaphylactic reactions have been reported. If any serious allergic or anaphylactic reaction occurs, Leukine therapy should immediately be discontinued and appropriate therapy initiated.

A syndrome characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia has been reported following the first administration of Leukine in a particular cycle. These signs have resolved with symptomatic treatment and usually do not recur with subsequent doses in the same cycle of treatment.

Stimulation of marrow precursors with Leukine may result in a rapid rise in white blood cell (WBC) count. If the ANC exceeds 20,000 cells/mm3 or if the platelet count exceeds 500,000/mm3, Leukine administration should be interrupted or the dose reduced by half. The decision to reduce the dose or interrupt treatment should be based on the clinical condition of the patient. Excessive blood counts have returned to normal or baseline levels within three to seven days following cessation of Leukine therapy. Twice weekly monitoring of CBC with differential (including examination for the presence of blast cells) should be performed to preclude development of excessive counts.

Growth Factor Potential

Leukine is a growth factor that primarily stimulates normal myeloid precursors. However, the possibility that Leukine can act as a growth factor for any tumor type, particularly myeloid malignancies, cannot be excluded. Because of the possibility of tumor growth potentiation, precaution should be exercised when using this drug in any malignancy with myeloid characteristics.

Should disease progression be detected during Leukine treatment, Leukine therapy should be discontinued.

Leukine has been administered to patients with myelodysplastic syndromes (MDS) in uncontrolled studies without evidence of increased relapse rates.13, 14, 15

Controlled studies have not been performed in patients with MDS.

Use in Patients Receiving Purged Bone Marrow

Leukine is effective in accelerating myeloid recovery in patients receiving bone marrow purged by anti-B lymphocyte monoclonal antibodies. Data obtained from uncontrolled studies suggest that if in vitro marrow purging with chemical agents causes a significant decrease in the number of responsive hematopoietic progenitors, the patient may not respond to Leukine. When the bone marrow purging process preserves a sufficient number of progenitors (>1.2 × 104/kg), a beneficial effect of Leukine on myeloid engraftment has been reported.16

Use in Patients Previously Exposed to Intensive Chemotherapy/Radiotherapy

In patients who before autologous BMT, have received extensive radiotherapy to hematopoietic sites for the treatment of primary disease in the abdomen or chest, or have been exposed to multiple myelotoxic agents (alkylating agents, anthracycline antibiotics and antimetabolites), the effect of Leukine on myeloid reconstitution may be limited.

Use in Patients with Malignancy Undergoing Leukine-Mobilized PBPC Collection

When using Leukine to mobilize PBPC, the limited in vitro data suggest that tumor cells may be released and reinfused into the patient in the leukapheresis product. The effect of reinfusion of tumor cells has not been well studied and the data are inconclusive.

Information for Patients

Leukine should be used under the guidance and supervision of a health care professional. However, when the physician determines that Leukine may be used outside of the hospital or office setting, persons who will be administering Leukine should be instructed as to the proper dose, and the method of reconstituting and administering Leukine (see DOSAGE AND ADMINISTRATION). If home use is prescribed, patients should be instructed in the importance of proper disposal and cautioned against the reuse of needles, syringes, drug product, and diluent. A puncture resistant container should be used by the patient for the disposal of used needles.

Patients should be informed of the serious and most common adverse reactions associated with Leukine administration (see ADVERSE REACTIONS). Female patients of childbearing potential should be advised of the possible risks to the fetus of Leukine (see PRECAUTIONS, Pregnancy Category C).

Laboratory Monitoring

Leukine can induce variable increases in WBC and/or platelet counts. In order to avoid potential complications of excessive leukocytosis (WBC >50,000 cells/mm3; ANC >20,000 cells/mm3), a CBC is recommended twice per week during Leukine therapy. Monitoring of renal and hepatic function in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least biweekly during Leukine administration. Body weight and hydration status should be carefully monitored during Leukine administration.

Drug Interaction

Interactions between Leukine and other drugs have not been fully evaluated. Drugs which may potentiate the myeloproliferative effects of Leukine, such as lithium and corticosteroids, should be used with caution.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies have not been conducted with Leukine to evaluate the carcinogenic potential or the effect on fertility.

Pregnancy (Category C)

Animal reproduction studies have not been conducted with Leukine. It is not known whether Leukine can cause fetal harm when administered to a pregnant woman or can affect reproductive capability. Leukine should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether Leukine is excreted in human milk. Because many drugs are excreted in human milk, Leukine should be administered to a nursing woman only if clearly needed.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established; however, available safety data indicate that Leukine does not exhibit any greater toxicity in pediatric patients than in adults. A total of 124 pediatric subjects between the ages of 4 months and 18 years have been treated with Leukine in clinical trials at doses ranging from 60–1,000 mcg/m2/day intravenously and 4–1,500 mcg/m2/day subcutaneously. In 53 pediatric patients enrolled in controlled studies at a dose of 250 mcg/m2/day by 2-hour IV infusion, the type and frequency of adverse events were comparable to those reported for the adult population. Liquid solutions containing benzyl alcohol (including liquid Leukine) or lyophilized Leukine reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates (see WARNINGS).

Geriatric Use

In the clinical trials, experience in older patients (age ≥65 years), was limited to the acute myelogenous leukemia (AML) study. Of the 52 patients treated with Leukine in this randomized study, 22 patients were age 65–70 years and 30 patients were age 55–64 years. The number of placebo patients in each age group were 13 and 33 patients respectively. This was not an adequate database from which determination of differences in efficacy endpoints or safety assessments could be reliably made and this clinical study was not designed to evaluate difference between these two age groups. Analyses of general trends in safety and efficacy were undertaken and demonstrate similar patterns for older (65–70 yrs) vs younger patients (55–64 yrs). Greater sensitivity of some older individuals cannot be ruled out.

Call your doctor for instructions if you miss a dose of Leukine.

Common side effects of Leukine include: hemophthalmos and ostealgia. See below for a comprehensive list of adverse effects.