Prokine

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Prokine uses

• Indications and usage
• Clinical experience
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Storage
• References
• Leukine® (sargramostim)
• Prokine reviews

INDICATIONS AND USAGE

Use Following Induction Chemotherapy in Acute Myelogenous Leukemia

Prokine is indicated for use following induction chemotherapy in older adult patients with acute myelogenous leukemia to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in death. The safety and efficacy of Prokine have not been assessed in patients with AML under 55 years of age.

The term acute myelogenous leukemia, also referred to as acute non-lymphocytic leukemia (ANLL), encompasses a heterogeneous group of leukemias arising from various non-lymphoid cell lines which have been defined morphologically by the French-American-British (FAB) system of classification.

Use in Mobilization and Following Transplantation of Autologous Peripheral Blood Progenitor Cells

Prokine is indicated for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis. Mobilization allows for the collection of increased numbers of progenitor cells capable of engraftment as compared with collection without mobilization. After myeloablative chemotherapy, the transplantation of an increased number of progenitor cells can lead to more rapid engraftment, which may result in a decreased need for supportive care. Myeloid reconstitution is further accelerated by administration of Prokine following peripheral blood progenitor cell transplantation.

Use in Myeloid Reconstitution After Autologous Bone Marrow Transplantation

Prokine is indicated for acceleration of myeloid recovery in patients with non-Hodgkin's lymphoma, acute lymphoblastic leukemia (ALL) and Hodgkin's disease undergoing autologous bone marrow transplantation (BMT). After autologous BMT in patients with NHL, ALL, or Hodgkin's disease, Prokine has been found to be safe and effective in accelerating myeloid engraftment, decreasing median duration of antibiotic administration, reducing the median duration of infectious episodes and shortening the median duration of hospitalization. Hematologic response to Prokine can be detected by complete blood count (CBC) with differential cell counts performed twice per week.

Use in Myeloid Reconstitution After Allogeneic Bone Marrow Transplantation

Prokine is indicated for acceleration of myeloid recovery in patients undergoing allogeneic BMT from HLA-matched related donors. Prokine has been found to be safe and effective in accelerating myeloid engraftment, reducing the incidence of bacteremia and other culture positive infections, and shortening the median duration of hospitalization.

Use in Bone Marrow Transplantation Failure or Engraftment Delay

Prokine is indicated in patients who have undergone allogeneic or autologous bone marrow transplantation (BMT) in whom engraftment is delayed or has failed. Prokine has been found to be safe and effective in prolonging survival of patients who are experiencing graft failure or engraftment delay, in the presence or absence of infection, following autologous or allogeneic BMT. Survival benefit may be relatively greater in those patients who demonstrate one or more of the following characteristics: autologous BMT failure or engraftment delay, no previous total body irradiation, malignancy other than leukemia or a multiple organ failure (MOF) score ≤ two (see CLINICAL EXPERIENCE ). Hematologic response to Prokine can be detected by complete blood count (CBC) with differential performed twice per week.

CLINICAL EXPERIENCE

Acute Myelogenous Leukemia

The safety and efficacy of Prokine in patients with AML who are younger than 55 years of age have not been determined. Based on Phase II data suggesting the best therapeutic effects could be achieved in patients at highest risk for severe infections and mortality while neutropenic, the Phase III clinical trial was conducted in older patients. The safety and efficacy of Prokine in the treatment of AML were evaluated in a multi-center, randomized, double-blind placebo-controlled trial of 99 newly diagnosed adult patients, 55–70 years of age, receiving induction with or without consolidation.⁶ A combination of standard doses of daunorubicin and ara-C (days 1–7) was administered during induction and high dose ara-C was administered days 1–6 as a single course of consolidation, if given. Bone marrow evaluation was performed on day 10 following induction chemotherapy. If hypoplasia with <5% blasts was not achieved, patients immediately received a second cycle of induction chemotherapy. If the bone marrow was hypoplastic with <5% blasts on day 10 or four days following the second cycle of induction chemotherapy, Prokine (250 mcg/m²/day) or placebo was given IV over four hours each day, starting four days after the completion of chemotherapy. Study drug was continued until an ANC ≥1500/mm³ for three consecutive days was attained or a maximum of 42 days. Prokine or placebo was also administered after the single course of consolidation chemotherapy if delivered (ara-C 3–6 weeks after induction following neutrophil recovery). Study drug was discontinued immediately if leukemic regrowth occurred.

Prokine significantly shortened the median duration of ANC <500/mm³ by 4 days and <1000/mm³ by 7 days following induction (see Table 1 ). 75% of patients receiving Prokine achieved ANC >500/mm³ by day 16, compared to day 25 for patients receiving placebo. The proportion of patients receiving one cycle (70%) or two cycles (30%) of induction was similar in both treatment groups; Prokine significantly shortened the median times to neutrophil recovery whether one cycle (12 versus 15 days) or two cycles (14 versus 23 days) of induction chemotherapy was administered. Median times to platelet (>20,000/mm³) and RBC transfusion independence were not significantly different between treatment groups.

Hematological Recovery (in Days): Induction
Dataset	Prokine n=52Patients with missing data censored. Median (25%, 75%)	Placebo n=47 Median (25%,75%)	p-valuep=Generalized Wilcoxon
ANC>500/mm3 2 patients on Prokine and 4 patients on placebo had missing values.	13 (11, 16)	17 (13, 25)	0.009
ANC>1000/mm3 2 patients on Prokine and 3 patients on placebo had missing values.	14 (12, 18)	21 (13, 34)	0.003
PLT>20,000/mm3 4 patients on placebo had missing values.	11 (7, 14)	12 (9, >42)	0.10
RBC3 patients on Prokine and 4 patients on placebo had missing values.	12 (9, 24)	14 (9, 42)	0.53

During the consolidation phase of treatment, Prokine did not shorten the median time to recovery of ANC to 500/mm³ (13 days) or 1000/mm³ (14.5 days) compared to placebo. There were no significant differences in time to platelet and RBC transfusion independence.

The incidence of severe infections and deaths associated with infections was significantly reduced in patients who received Prokine. During induction or consolidation, 27 of 52 patients receiving Prokine and 35 of 47 patients receiving placebo had at least one grade 3, 4 or 5 infection (p=0.02). Twenty-five patients receiving Prokine and 30 patients receiving placebo experienced severe and fatal infections during induction only. There were significantly fewer deaths from infectious causes in the Prokine arm (3 versus 11, p=0.02). The majority of deaths in the placebo group were associated with fungal infections with pneumonia as the primary infection.

Disease outcomes were not adversely affected by the use of Prokine. The proportion of patients achieving complete remission (CR) was higher in the Prokine group (69% as compared to 55% for the placebo group), but the difference was not significant (p=0.21). There was no significant difference in relapse rates; 12 of 36 patients who received Prokine and five of 26 patients who received placebo relapsed within 180 days of documented CR (p=0.26). The overall median survival was 378 days for patients receiving Prokine and 268 days for those on placebo (p=0.17). The study was not sized to assess the impact of Prokine treatment on response or survival.

Mobilization and Engraftment of PBPC

A retrospective review was conducted of data from patients with cancer undergoing collection of peripheral blood progenitor cells (PBPC) at a single transplant center. Mobilization of PBPC and myeloid reconstitution post-transplant were compared between four groups of patients (n=196) receiving Prokine for mobilization and a historical control group who did not receive any mobilization treatment [progenitor cells collected by leukapheresis without mobilization (n=100)]. Sequential cohorts received Prokine. The cohorts differed by dose (125 or 250 mcg/m²/day), route (IV over 24 hours or SC) and use of Prokine post-transplant. Leukaphereses were initiated for all mobilization groups after the WBC reached 10,000/mm³. Leukaphereses continued until both a minimum number of mononucleated cells (MNC) were collected (6.5 or 8.0 × 10⁸/kg body weight) and a minimum number of phereses (5–8) were performed. Both minimum requirements varied by treatment cohort and planned conditioning regimen. If subjects failed to reach a WBC of 10,000 cells/mm³ by day five, another cytokine was substituted for Prokine; these subjects were all successfully leukapheresed and transplanted. The most marked mobilization and post-transplant effects were seen in patients administered the higher dose of Prokine (250 mcg/m²) either IV (n=63) or SC (n=41).

PBPCs from patients treated at the 250 mcg/m²/day dose had significantly higher number of granulocyte-macrophage colony-forming units (CFU-GM) than those collected without mobilization. The mean value after thawing was 11.41 × 10⁴ CFU-GM/kg for all LEUKINE-mobilized patients, compared to 0.96 × 10⁴/kg for the non-mobilized group. A similar difference was observed in the mean number of erythrocyte burst-forming units (BFU-E) collected (23.96 × 10⁴/kg for patients mobilized with 250 mcg/m² doses of Prokine administered SC vs. 1.63 × 10⁴/kg for non-mobilized patients).

After transplantation, mobilized subjects had shorter times to myeloid engraftment and fewer days between transplantation and the last platelet transfusion compared to non-mobilized subjects. Neutrophil recovery (ANC >500/mm³) was more rapid in patients administered Prokine following PBPC transplantation with LEUKINE-mobilized cells (see Table 2 ). Mobilized patients also had fewer days to the last platelet transfusion and last RBC transfusion, and a shorter duration of hospitalization than did non-mobilized subjects.

ANC and Platelet Recovery after PBPC Transplant
	Route for Mobilization	Post-transplant Prokine	ENGRAFTMENT (median value in days)
			ANC>500/mm3	Last platelet transfusion
No Mobilization	-	no	29	28
Prokine	IV	no	21	24
250 mcg/m2	IV	yes	12	19
	SC	yes	12	17

A second retrospective review of data from patients undergoing PBPC at another single transplant center was also conducted. Prokine was given SC at 250 mcg/m²/day once a day (n=10) or twice a day (n=21) until completion of the phereses. Phereses were begun on day 5 of Prokine administration and continued until the targeted MNC count of 9 × 10⁸/kg or CD34+ cell count of 1 × 10⁶/kg was reached. There was no difference in CD34+ cell count in patients receiving Prokine once or twice a day. The median time to ANC>500/mm³ was 12 days and to platelet recovery (>25,000/mm³) was 23 days.

Survival studies comparing mobilized study patients to the nonmobilized patients and to an autologous historical bone marrow transplant group showed no differences in median survival time.

Autologous Bone Marrow Transplantation⁷

Following a dose-ranging Phase I/II trial in patients undergoing autologous BMT for lymphoid malignancies,^{8, 9} three single center, randomized, placebo-controlled and double-blinded studies were conducted to evaluate the safety and efficacy of Prokine for promoting hematopoietic reconstitution following autologous BMT. A total of 128 patients were enrolled in these three studies. The majority of the patients had lymphoid malignancy (87 NHL, 17 ALL), 23 patients had Hodgkin's disease, and one patient had acute myeloblastic leukemia (AML). In 72 patients with NHL or ALL, the bone marrow harvest was purged prior to storage with one of several monoclonal antibodies. No chemical agent was used for in vitro treatment of the bone marrow. Preparative regimens in the three studies included cyclophosphamide (total dose 120–150 mg/kg) and total body irradiation (total dose 1,200–1,575 rads). Other regimens used in patients with Hodgkin's disease and NHL without radiotherapy consisted of three or more of the following in combination (expressed as total dose): cytosine arabinoside (400 mg/m²) and carmustine (300 mg/m²), cyclophosphamide (140–150 mg/kg), hydroxyurea (4.5 grams/m²) and etoposide (375–450 mg/m²).

Compared to placebo, administration of Prokine in two studies (n=44 and 47) significantly improved the following hematologic and clinical endpoints: time to neutrophil engraftment, duration of hospitalization and infection experience or antibacterial usage. In the third study (n=37) there was a positive trend toward earlier myeloid engraftment in favor of Prokine. This latter study differed from the other two in having enrolled a large number of patients with Hodgkin's disease who had also received extensive radiation and chemotherapy prior to harvest of autologous bone marrow. A subgroup analysis of the data from all three studies revealed that the median time to engraftment for patients with Hodgkin's disease, regardless of treatment, was six days longer when compared to patients with NHL and ALL, but that the overall beneficial Prokine treatment effect was the same. In the following combined analysis of the three studies, these two subgroups (NHL and ALL vs. Hodgkin's disease) are presented separately.

Autologous BMT: Combined Analysis from Placebo-Controlled Clinical Trials of Responses in Patients with NHL and ALL Median Values (days)
	ANC ≥500/mm3	ANC ≥1000/mm3	Duration of Hospitalization	Duration of Infection	Duration of Antibacterial Therapy
Note: The single AML patient was not included.
Prokine (n=54)	18p <0.05 Wilcoxon or CMH ridit chi-squared p <0.05 Log rank	24	25	1	21
Placebo (n=50)	24	32	31	4	25

Patients with Lymphoid Malignancy (Non-Hodgkin's Lymphoma and Acute Lymphoblastic Leukemia)

Myeloid engraftment (absolute neutrophil count [ANC] ≥500 cells/mm³) in 54 patients receiving Prokine was observed 6 days earlier than in 50 patients treated with placebo (see Table 3 ). Accelerated myeloid engraftment was associated with significant clinical benefits. The median duration of hospitalization was six days shorter for the Prokine group than for the placebo group. Median duration of infectious episodes (defined as fever and neutropenia; or two positive cultures of the same organism; or fever >38°C and one positive blood culture; or clinical evidence of infection) was three days less in the group treated with Prokine. The median duration of antibacterial administration in the post-transplantation period was four days shorter for the patients treated with Prokine than for placebo-treated patients. The study was unable to detect a significant difference between the treatment groups in rate of disease relapse 24 months post-transplantation. As a group, leukemic subjects receiving Prokine derived less benefit than NHL subjects. However, both the leukemic and NHL groups receiving Prokine engrafted earlier than controls.

Patients with Hodgkin's Disease

If patients with Hodgkin's disease are analyzed separately, a trend toward earlier myeloid engraftment is noted. LEUKINE-treated patients engrafted earlier than the placebo-treated patients (p=0.189, Wilcoxon) but the number of patients was small (n=22).

Allogeneic Bone Marrow Transplantation

A multi-center, randomized, placebo-controlled, and double-blinded study was conducted to evaluate the safety and efficacy of Prokine for promoting hematopoietic reconstitution following allogeneic BMT. A total of 109 patients (53 Prokine, 56 placebo) were enrolled in the study. Twenty-three patients (11 Prokine, 12 placebo) were 18 years old or younger. Sixty-seven patients had myeloid malignancies (33 AML, 34 CML), 17 had lymphoid malignancies (12 ALL, 5 NHL), three patients had Hodgkin's disease, six had multiple myeloma, nine had myelodysplastic disease, and seven patients had aplastic anemia. In 22 patients at one of the seven study sites, bone marrow harvests were depleted of T cells. Preparative regimens included cyclophosphamide, busulfan, cytosine arabinoside, etoposide, methotrexate, corticosteroids, and asparaginase. Some patients also received total body, splenic, or testicular irradiation. Primary graft-versus-host disease (GVHD) prophylaxis was cyclosporine A and a corticosteroid.

Accelerated myeloid engraftment was associated with significant laboratory and clinical benefits. Compared to placebo, administration of Prokine significantly improved the following: time to neutrophil engraftment, duration of hospitalization, number of patients with bacteremia and overall incidence of infection (see Table 4 ).

Allogeneic BMT: Analysis of Data from Placebo-Controlled Clinical Trial Median Values (days or number of patients)
	ANC ≥ 500/mm3	ANC ≥ 1000/mm3	Number of Patients with Infections	Number of Patients with Bacteremia	Days of Hospitalization
Prokine (n=53)	13p <0.05 generalized Wilcoxon test	14	30	9p <0.05 simple chi-square test	25
Placebo (n=56)	17	19	42	19	26

Median time to myeloid engraftment (ANC ≥ 500 cells/mm³) in 53 patients receiving Prokine was 4 four days less than in 56 patients treated with placebo (see Table 4 ). The number of patients with bacteremia and infection was significantly lower in the Prokine group compared to the placebo group (9/53 versus 19/56 and 30/53 versus 42/56, respectively). There were a number of secondary laboratory and clinical endpoints. Of these, only the incidence of severe (grade 3/4) mucositis was significantly improved in the Prokine group (4/53) compared to the placebo group (16/56) at p<0.05. LEUKINE-treated patients also had a shorter median duration of post-transplant IV antibiotic infusions, and shorter median number of days to last platelet and RBC transfusions compared to placebo patients, but none of these differences reached statistical significance.

Bone Marrow Transplantation Failure or Engraftment Delay

A historically-controlled study was conducted in patients experiencing graft failure following allogeneic or autologous BMT to determine whether Prokine improved survival after BMT failure.

Three categories of patients were eligible for this study:

• patients displaying a delay in engraftment ;
• patients displaying a delay in engraftment (ANC ≤ 100 cells/mm³ by day 21 post-transplantation) and who had evidence of an active infection; and
• patients who lost their marrow graft after a transient engraftment (manifested by an average of ANC ≥ 500 cells/mm³ for at least one week followed by loss of engraftment with ANC < 500 cells/mm³ for at least one week beyond day 21 post-transplantation).

A total of 140 eligible patients from 35 institutions were treated with Prokine and evaluated in comparison to 103 historical control patients from a single institution. One hundred sixty-three patients had lymphoid or myeloid leukemia, 24 patients had non-Hodgkin's lymphoma, 19 patients had Hodgkin's disease and 37 patients had other diseases, such as aplastic anemia, myelodysplasia or non-hematologic malignancy. The majority of patients (223 out of 243) had received prior chemotherapy with or without radiotherapy and/or immunotherapy prior to preparation for transplantation.

One hundred day survival was improved in favor of the patients treated with Prokine after graft failure following either autologous or allogeneic BMT. In addition, the median survival was improved by greater than two-fold. The median survival of patients treated with Prokine after autologous failure was 474 days versus 161 days for the historical patients. Similarly, after allogeneic failure, the median survival was 97 days with Prokine treatment and 35 days for the historical controls. Improvement in survival was better in patients with fewer impaired organs.

The MOF score is a simple clinical and laboratory assessment of seven major organ systems: cardiovascular, respiratory, gastrointestinal, hematologic, renal, hepatic and neurologic.¹⁰ Assessment of the MOF score is recommended as an additional method of determining the need to initiate treatment with Prokine in patients with graft failure or delay in engraftment following autologous or allogeneic BMT (see Table 5 ).

Median Survival by Multiple Organ Failure (MOF) Category Median Survival (days)
	MOF ≤ 2 Organs	MOF > 2 Organs	MOF (Composite of Both Groups)
Autologous BMT
Prokine	474 (n=58)	78.5 (n=10)	474 (n=68)
Historical	165 (n=14)	39 (n=3)	161 (n=17)
Allogeneic BMT
Prokine	174 (n=50)	27 (n=22)	97 (n=72)
Historical	52.5(n=60)	15.5(n=26)	35 (n=86)

Factors that Contribute to Survival

The probability of survival was relatively greater for patients with any one of the following characteristics: autologous BMT failure or delay in engraftment, exclusion of total body irradiation from the preparative regimen, a non-leukemic malignancy or MOF score ≤ two (zero, one or two dysfunctional organ systems). Leukemic subjects derived less benefit than other subjects.

CONTRAINDICATIONS

Prokine is contraindicated:

• in patients with excessive leukemic myeloid blasts in the bone marrow or peripheral blood (≥ 10%);
• in patients with known hypersensitivity to GM-CSF, yeast-derived products or any component of the product;
• for concomitant use with chemotherapy and radiotherapy.

Due to the potential sensitivity of rapidly dividing hematopoietic progenitor cells, Prokine should not be administered simultaneously with cytotoxic chemotherapy or radiotherapy or within 24 hours preceding or following chemotherapy or radiotherapy. In one controlled study, patients with small cell lung cancer received Prokine and concurrent thoracic radiotherapy and chemotherapy or the identical radiotherapy and chemotherapy without Prokine. The patients randomized to Prokine had significantly higher incidence of adverse events, including higher mortality and a higher incidence of grade 3 and 4 infections and grade 3 and 4 thrombocytopenia.¹¹

WARNINGS

Pediatric Use

Benzyl alcohol is a constituent of liquid Prokine and Bacteriostatic Water for Injection diluent. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants. Liquid solutions containing benzyl alcohol or lyophilized Prokine reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ).

Fluid Retention

Edema, capillary leak syndrome, pleural and/or pericardial effusion have been reported in patients after Prokine administration. In 156 patients enrolled in placebo-controlled studies using Prokine at a dose of 250 mcg/m²/day by 2-hour IV infusion, the reported incidences of fluid retention (LEUKINE vs. placebo) were as follows: peripheral edema, 11% vs. 7%; pleural effusion, 1% vs. 0%; and pericardial effusion, 4% vs. 1%. Capillary leak syndrome was not observed in this limited number of studies; based on other uncontrolled studies and reports from users of marketed Prokine, the incidence is estimated to be less than 1%. In patients with preexisting pleural and pericardial effusions, administration of Prokine may aggravate fluid retention; however, fluid retention associated with or worsened by Prokine has been reversible after interruption or dose reduction of Prokine with or without diuretic therapy. Prokine should be used with caution in patients with preexisting fluid retention, pulmonary infiltrates or congestive heart failure.

Respiratory Symptoms

Sequestration of granulocytes in the pulmonary circulation has been documented following Prokine infusion¹² and dyspnea has been reported occasionally in patients treated with Prokine. Special attention should be given to respiratory symptoms during or immediately following Prokine infusion, especially in patients with preexisting lung disease. In patients displaying dyspnea during Prokine administration, the rate of infusion should be reduced by half. If respiratory symptoms worsen despite infusion rate reduction, the infusion should be discontinued. Subsequent IV infusions may be administered following the standard dose schedule with careful monitoring. Prokine should be administered with caution in patients with hypoxia.

Cardiovascular Symptoms

Occasional transient supraventricular arrhythmia has been reported in uncontrolled studies during Prokine administration, particularly in patients with a previous history of cardiac arrhythmia. However, these arrhythmias have been reversible after discontinuation of Prokine. Prokine should be used with caution in patients with preexisting cardiac disease.

Renal and Hepatic Dysfunction

In some patients with preexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of Prokine has induced elevation of serum creatinine or bilirubin and hepatic enzymes. Dose reduction or interruption of Prokine administration has resulted in a decrease to pretreatment values. However, in controlled clinical trials the incidences of renal and hepatic dysfunction were comparable between Prokine (250 mcg/m²/day by 2-hour IV infusion) and placebo-treated patients. Monitoring of renal and hepatic function in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least every other week during Prokine administration.

PRECAUTIONS

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, Prokine 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 Prokine 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 Prokine may result in a rapid rise in white blood cell count. If the ANC exceeds 20,000 cells/mm³ or if the platelet count exceeds 500,000/mm³, Prokine 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 Prokine 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

Prokine is a growth factor that primarily stimulates normal myeloid precursors. However, the possibility that Prokine 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 Prokine treatment, Prokine therapy should be discontinued.

Prokine 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

Prokine 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 Prokine. When the bone marrow purging process preserves a sufficient number of progenitors, a beneficial effect of Prokine 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 Prokine on myeloid reconstitution may be limited.

Use in Patients with Malignancy Undergoing LEUKINE-Mobilized PBPC Collection

When using Prokine 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.

Immunogenicity

Treatment with Prokine may induce neutralizing anti-drug antibodies. The incidence of anti-sargramostim neutralizing antibodies may be related to duration of exposure to Prokine. In a study of patients with normal neutrophil count and a solid tumor in complete response treated with Prokine for up to 12 months, 41% of 41 evaluable patients developed anti-sargramostim neutralizing antibodies and the myelostimulatory effect of Prokine was not sustained by day 155 as assessed by white blood cell count. Use Prokine for the shortest duration required.

Information for Patients

Prokine should be used under the guidance and supervision of a health care professional. However, when the physician determines that Prokine may be used outside of the hospital or office setting, persons who will be administering Prokine should be instructed as to the proper dose, and the method of reconstituting and administering Prokine (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 Prokine administration (see ADVERSE REACTIONS ). Female patients of childbearing potential should be advised of the possible risks to the fetus of Prokine (see PRECAUTIONS, Pregnancy Category C ).

Laboratory Monitoring

Prokine can induce variable increases in WBC and/or platelet counts. In order to avoid potential complications of excessive leukocytosis, a CBC is recommended twice per week during Prokine 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 Prokine administration. Body weight and hydration status should be carefully monitored during Prokine administration.

Drug Interaction

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Pregnancy

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

Nursing Mothers

It is not known whether Prokine is excreted in human milk. Because many drugs are excreted in human milk, Prokine 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 Prokine 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 Prokine 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 or lyophilized Prokine 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 Prokine 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.

ADVERSE REACTIONS

Autologous and Allogeneic Bone Marrow Transplantation

Prokine is generally well tolerated. In three placebo-controlled studies enrolling a total of 156 patients after autologous BMT or peripheral blood progenitor cell transplantation, events reported in at least 10% of patients who received IV Prokine or placebo were as reported in Table 6 .

Percent of AuBMT Patients Reporting Events
Events by Body System	Prokine	Placebo (n=77)	Events by Body System	Prokine (n=79)	Placebo (n=77)
Body, General			Metabolic, Nutritional Disorder
Fever	95	96	Edema	34	35
Mucous membrane disorder	75	78	Peripheral edema	11	7
Asthenia	66	51	Respiratory System
Malaise	57	51	Dyspnea	28	31
Sepsis	11	14	Lung disorder	20	23
Digestive System			Hemic and Lymphatic System
Nausea	90	96	Blood dyscrasia	25	27
Diarrhea	89	82	Cardiovascular System
Vomiting	85	90	Hemorrhage	23	30
Anorexia	54	58	Urogenital System
GI disorder	37	47	Urinary tract disorder	14	13
GI hemorrhage	27	33	Kidney function abnormal	8	10
Stomatitis	24	29	Nervous System
Liver damage	13	14	CNS disorder	11	16
Skin and Appendages
Alopecia	73	74
Rash	44	38

No significant differences were observed between Prokine and placebo-treated patients in the type or frequency of laboratory abnormalities, including renal and hepatic parameters. In some patients with preexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of Prokine has induced elevation of serum creatinine or bilirubin and hepatic enzymes (see WARNINGS ). In addition, there was no significant difference in relapse rate and 24 month survival between the Prokine and placebo-treated patients.

In the placebo-controlled trial of 109 patients after allogeneic BMT, events reported in at least 10% of patients who received IV Prokine or placebo were as reported in Table 7 .

Percent of Allogeneic BMT Patients Reporting Events
Events by Body System	Prokine (n=53)	Placebo (n=56)	Events by Body System	Prokine (n=53)	Placebo (n=56)
Body, General			Metabolic/Nutritional Disorders
Fever	77	80	Bilirubinemia	30	27
Abdominal pain	38	23	Hyperglycemia	25	23
Headache	36	36	Peripheral edema	15	21
Chills	25	20	Increased creatinine	15	14
Pain	17	36	Hypomagnesemia	15	9
Asthenia	17	20	Increased SGPT	13	16
Chest pain	15	9	Edema	13	11
Back pain	9	18	Increased alk. phosphatase	8	14
Digestive System			Respiratory System
Diarrhea	81	66	Pharyngitis	23	13
Nausea	70	66	Epistaxis	17	16
Vomiting	70	57	Dyspnea	15	14
Stomatitis	62	63	Rhinitis	11	14
Anorexia	51	57	Hemic and Lymphatic System
Dyspepsia	17	20	Thrombocytopenia	19	34
Hematemesis	13	7	Leukopenia	17	29
Dysphagia	11	7	Petechia	6	11
GI hemorrhage	11	5	Agranulocytosis	6	11
Constipation	8	11	Urogenital System
Skin and Appendages			Hematuria	9	21
Rash	70	73	Nervous System
Alopecia	45	45	Paresthesia	11	13
Pruritis	23	13	Insomnia	11	9
Musculo-skeletal System			Anxiety	11	2
Bone pain	21	5	Laboratory Abnormalities Grade 3 and 4 laboratory abnormalities only. Denominators may vary due to missing laboratory measurements.
Arthralgia	11	4	High glucose	41	49
Special Senses			Low albumin	27	36
Eye hemorrhage	11	0	High BUN	23	17
Cardiovascular System			Low calcium	2	7
Hypertension	34	32	High cholesterol	17	8
Tachycardia	11	9

There were no significant differences in the incidence or severity of GVHD, relapse rates and survival between the Prokine and placebo-treated patients. Adverse events observed for the patients treated with Prokine in the historically-controlled BMT failure study were similar to those reported in the placebo-controlled studies. In addition, headache (26%), pericardial effusion (25%), arthralgia (21%) and myalgia (18%) were also reported in patients treated with Prokine in the graft failure study.

In uncontrolled Phase I/II studies with Prokine in 215 patients, the most frequent adverse events were fever, asthenia, headache, bone pain, chills and myalgia. These systemic events were generally mild or moderate and were usually prevented or reversed by the administration of analgesics and antipyretics such as acetaminophen. In these uncontrolled trials, other infrequent events reported were dyspnea, peripheral edema, and rash.

Reports of events occurring with marketed Prokine include arrhythmia, fainting, eosinophilia, dizziness, hypotension, injection site reactions, pain (including abdominal, back, chest, and joint pain), tachycardia, thrombosis, and transient liver function abnormalities.

In patients with preexisting edema, capillary leak syndrome, pleural and/or pericardial effusion, administration of Prokine may aggravate fluid retention (see WARNINGS ). Body weight and hydration status should be carefully monitored during Prokine administration.

Adverse events observed in pediatric patients in controlled studies were comparable to those observed in adult patients.

Acute Myelogenous Leukemia

Adverse events reported in at least 10% of patients who received Prokine or placebo were as reported in Table 8 .

Percent of AML Patients Reporting Events
Events by Body System	Prokine (n=52)	Placebo (n=47)	Events by Body System	Prokine (n=52)	Placebo (n=47)
Body, General			Metabolic/Nutritional Disorder
Fever (no infection)	81	74	Metabolic	58	49
Infection	65	68	Edema	25	23
Weight loss	37	28	Respiratory System
Weight gain	8	21	Pulmonary	48	64
Chills	19	26	Hemic and Lymphatic System
Allergy	12	15	Coagulation	19	21
Sweats	6	13	Cardiovascular System
Digestive System			Hemorrhage	29	43
Nausea	58	55	Hypertension	25	32
Liver	77	83	Cardiac	23	32
Diarrhea	52	53	Hypotension	13	26
Vomiting	46	34	Urogenital System
Stomatitis	42	43	GU	50	57
Anorexia	13	11	Nervous System
Abdominal distention	4	13	Neuro-clinical	42	53
Skin and Appendages			Neuro-motor	25	26
Skin	77	45	Neuro-psych	15	26
Alopecia	37	51	Neuro-sensory	6	11

Nearly all patients reported leukopenia, thrombocytopenia and anemia. The frequency and type of adverse events observed following induction were similar between Prokine and placebo groups. The only significant difference in the rates of these adverse events was an increase in skin associated events in the Prokine group (p=0.002). No significant differences were observed in laboratory results, renal or hepatic toxicity. No significant differences were observed between the Prokine and placebo-treated patients for adverse events following consolidation. There was no significant difference in response rate or relapse rate.

In a historically-controlled study of 86 patients with acute myelogenous leukemia (AML), the Prokine treated group exhibited an increased incidence of weight gain (p=0.007), low serum proteins and prolonged prothrombin time (p=0.02) when compared to the control group. Two Prokine treated patients had progressive increase in circulating monocytes and promonocytes and blasts in the marrow which reversed when Prokine was discontinued. The historical control group exhibited an increased incidence of cardiac events (p=0.018), liver function abnormalities (p=0.008), and neurocortical hemorrhagic events (p=0.025).¹⁵

Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity with Prokine. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, duration of treatment, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Prokine in the studies described below with the incidence of antibodies in other studies or other products may be misleading.

In 214 patients with a variety of underlying diseases, neutralizing anti-sargramostim antibodies were detected in 5 patients after receiving Prokine by continuous IV infusion (3 patients) or subcutaneous injection (2 patients) for 28 to 84 days in multiple courses (as assessed by GM-CSF dependent human cell-line proliferation assay). All 5 patients had impaired hematopoiesis before the administration of Prokine and consequently the effect of the development of anti-sargramostim antibodies on normal hematopoiesis could not be assessed.

Antibody studies of 75 patients with Crohn's disease, with normal hematopoiesis and no other immunosuppressive drugs, receiving Prokine daily for 8 weeks by subcutaneous injection, showed 1 patient (1.3%) with detectable neutralizing anti-sargramostim antibodies (as assessed by GM-CSF dependent human cell-line proliferation assay).

In an experimental use trial where Prokine was given for an extended period, 53 patients with melanoma in complete remission (an unapproved use) received adjuvant therapy with Prokine 125 mcg/m² once daily (maximum dose 250 mcg) from day 1 to 14 every 28 days for 1 year. Serum samples from patients assessed at Day 0, 2 weeks, 1 month, and 5 and/or 12 months were tested retrospectively for the presence of anti-sargramostim antibodies. Of 43 evaluable patients (having at least 3 time-point samples post treatment), 42 (97.7%) developed anti-sargramostim binding antibody as assessed by ELISA and confirmed using an immunoprecipitation assay. Of these 42 patients, 41 had sufficient sample and were further tested: 34 patients (82.9%) developed anti-sargramostim neutralizing antibodies (as determined by a cell based luciferase reporter gene neutralizing antibody assay); 17 (50%) of these patients did not have a sustained pharmacodynamic effect of Prokine by day 155 as assessed by white blood cell counts. This study provided limited assessment of the impact of antibody formation on the safety and efficacy of Prokine.

Serious allergic and anaphylactoid reactions have been reported with Prokine but the rate of occurrence of antibodies in such patients has not been assessed.

Overdosage

The maximum amount of Prokine that can be safely administered in single or multiple doses has not been determined. Doses up to 100 mcg/kg/day (4,000 mcg/m²/day or 16 times the recommended dose) were administered to four patients in a Phase I uncontrolled clinical study by continuous IV infusion for 7 to 18 days. Increases in WBC up to 200,000 cells/mm³ were observed. Adverse events reported were dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache and chills. All these events were reversible after discontinuation of Prokine.

In case of overdosage, Prokine therapy should be discontinued and the patient carefully monitored for WBC increase and respiratory symptoms.

To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 1-888-4RX-LEUKINE or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

DOSAGE AND ADMINISTRATION

Neutrophil Recovery Following Chemotherapy in Acute Myelogenous Leukemia

The recommended dose is 250 mcg/m²/day administered intravenously over a 4 hour period starting approximately on day 11 or four days following the completion of induction chemotherapy, if the day 10 bone marrow is hypoplastic with <5% blasts. If a second cycle of induction chemotherapy is necessary, Prokine should be administered approximately four days after the completion of chemotherapy if the bone marrow is hypoplastic with <5% blasts. Prokine should be continued until an ANC >1500 cells/mm³ for 3 consecutive days or a maximum of 42 days. Prokine should be discontinued immediately if leukemic regrowth occurs. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates.

In order to avoid potential complications of excessive leukocytosis a CBC with differential is recommended twice per week during Prokine therapy. Prokine treatment should be interrupted or the dose reduced by half if the ANC exceeds 20,000 cells/mm³.

Mobilization of Peripheral Blood Progenitor Cells

The recommended dose is 250 mcg/m²/day administered IV over 24 hours or SC once daily. Dosing should continue at the same dose through the period of PBPC collection. The optimal schedule for PBPC collection has not been established. In clinical studies, collection of PBPC was usually begun by day 5 and performed daily until protocol specified targets were achieved (see CLINICAL EXPERIENCE , Mobilization and Engraftment of PBPC ). If WBC > 50,000 cells/mm³, the Prokine dose should be reduced by 50%. If adequate numbers of progenitor cells are not collected, other mobilization therapy should be considered.

Post Peripheral Blood Progenitor Cell Transplantation

The recommended dose is 250 mcg/m²/day administered IV over 24 hours or SC once daily beginning immediately following infusion of progenitor cells and continuing until an ANC>1500 cells/mm³ for three consecutive days is attained.

Myeloid Reconstitution After Autologous or Allogeneic Bone Marrow Transplantation

The recommended dose is 250 mcg/m²/day administered IV over a 2-hour period beginning two to four hours after bone marrow infusion, and not less than 24 hours after the last dose of chemotherapy or radiotherapy. Patients should not receive Prokine until the post marrow infusion ANC is less than 500 cells/mm³. Prokine should be continued until an ANC >1500 cells/mm³ for three consecutive days is attained. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates. Prokine should be discontinued immediately if blast cells appear or disease progression occurs.

In order to avoid potential complications of excessive leukocytosis a CBC with differential is recommended twice per week during Prokine therapy. Prokine treatment should be interrupted or the dose reduced by 50% if the ANC exceeds 20,000 cells/mm³.

Bone Marrow Transplantation Failure or Engraftment Delay

The recommended dose is 250 mcg/m²/day for 14 days as a 2-hour IV infusion. The dose can be repeated after 7 days off therapy if engraftment has not occurred. If engraftment still has not occurred, a third course of 500 mcg/m²/day for 14 days may be tried after another 7 days off therapy. If there is still no improvement, it is unlikely that further dose escalation will be beneficial. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates. Prokine should be discontinued immediately if blast cells appear or disease progression occurs.

In order to avoid potential complications of excessive leukocytosis (WBC > 50,000 cells/mm³, ANC > 20,000 cells/mm³) a CBC with differential is recommended twice per week during Prokine therapy. Prokine treatment should be interrupted or the dose reduced by half if the ANC exceeds 20,000 cells/mm³.

Preparation of Prokine

• Liquid Prokine is formulated as a sterile, preserved (1.1% benzyl alcohol), injectable solution (500 mcg/mL) in a vial. Lyophilized Prokine is a sterile, white, preservative-free powder (250 mcg) that requires reconstitution with 1 mL Sterile Water for Injection, USP, or 1 mL Bacteriostatic Water for Injection, USP.
• Liquid Prokine may be stored for up to 20 days at 2–8°C once the vial has been entered. Discard any remaining solution after 20 days.
• Lyophilized Prokine (250 mcg) should be reconstituted aseptically with 1.0 mL of diluent. The contents of vials reconstituted with different diluents should not be mixed together.
  

  Sterile Water for Injection, USP (without preservative): Lyophilized Prokine vials contain no antibacterial preservative, and therefore solutions prepared with Sterile Water for Injection, USP should be administered as soon as possible, and within 6 hours following reconstitution and/or dilution for IV infusion. The vial should not be re-entered or reused. Do not save any unused portion for administration more than 6 hours following reconstitution. Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol): Reconstituted solutions prepared with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) may be stored for up to 20 days at 2–8°C prior to use. Discard reconstituted solution after 20 days. Previously reconstituted solutions mixed with freshly reconstituted solutions must be administered within 6 hours following mixing. Preparations containing benzyl alcohol (including liquid Prokine and lyophilized Prokine reconstituted with Bacteriostatic Water for Injection) should not be used in neonates (see WARNINGS ).

• During reconstitution of lyophilized Prokine the diluent should be directed at the side of the vial and the contents gently swirled to avoid foaming during dissolution. Avoid excessive or vigorous agitation; do not shake.
• Prokine should be used for SC injection without further dilution. Dilution for IV infusion should be performed in 0.9% Sodium Chloride Injection, USP. If the final concentration of Prokine is below 10 mcg/mL, Albumin (Human) at a final concentration of 0.1% should be added to the saline prior to addition of Prokine to prevent adsorption to the components of the drug delivery system. To obtain a final concentration of 0.1% Albumin (Human), add 1 mg Albumin (Human) per 1 mL 0.9% Sodium Chloride Injection, USP (e.g., use 1 mL 5% Albumin [Human] in 50 mL 0.9% Sodium Chloride Injection, USP).
• An in-line membrane filter should NOT be used for intravenous infusion of Prokine.
• Store liquid Prokine and reconstituted lyophilized Prokine solutions under refrigeration at 2–8°C (36–46°F); DO NOT FREEZE.
• In the absence of compatibility and stability information, no other medication should be added to infusion solutions containing Prokine. Use only 0.9% Sodium Chloride Injection, USP to prepare IV infusion solutions.
• Aseptic technique should be employed in the preparation of all Prokine solutions. To assure correct concentration following reconstitution, care should be exercised to eliminate any air bubbles from the needle hub of the syringe used to prepare the diluent. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter is present or the solution is discolored, the vial should not be used.

HOW SUPPLIED

Liquid Prokine is available in vials containing 500 mcg/mL (2.8 × 10⁶ IU/mL) Prokine. Lyophilized Prokine is available in vials containing 250 mcg (1.4 × 10⁶ IU/vial) Prokine.

Each dosage form is supplied as follows:

Lyophilized Prokine

Carton of five vials of lyophilized Prokine 250 mcg (NDC 0024-5843-05)

Liquid Prokine

Carton of one multiple-use vial; each vial contains 1 mL of preserved 500 mcg/mL liquid Prokine (NDC 0024-5844-01)

Carton of five multiple-use vials; each vial contains 1 mL of preserved 500 mcg/mL liquid Prokine (NDC 0024-5844-05)

STORAGE

Prokine should be refrigerated at 2–8°C (36–46°F). Do not freeze or shake. Do not use beyond the expiration date printed on the vial.

REFERENCES

• Metcalf D. The molecular biology and functions of the granulocyte-macrophage colony stimulating factors. Blood 1986; 67(2):257–267.
• Park LS, Friend D, Gillis S, Urdal DL. Characterization of the cell surface receptor for human granulocyte/macrophage colony stimulating factor. J Exp Med 1986; 164:251–262.
• Grabstein KH, Urdal DL, Tushinski RJ, et al. Induction of macrophage tumoricidal activity by granulocyte-macrophage colony-stimulating factors. Science 1986; 232:506–508.
• Reed SG, Nathan CF, Pihl DL, et al. Recombinant granulocyte/macrophage colony-stimulating factor activates macrophages to inhibit Trypanosoma cruzi and release hydrogen peroxide. J Exp Med 1987; 166:1734–1746.
• Data on file Bayer HealthCare Pharmaceuticals
• Rowe JM, Andersen JW, Mazza JJ, et al. A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (>55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood 1995; 86(2):457–462.
• Nemunaitis J, Rabinowe SN, Singer JW, et al. Recombinant human granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid malignancy: Pooled results of a randomized, double-blind, placebo controlled trial. NEJM 1991; 324(25):1773–1778.
• Nemunaitis J, Singer JW, Buckner CD, et al. Use of recombinant human granulocyte-macrophage colony stimulating factor in autologous bone marrow transplantation for lymphoid malignancies. Blood 1988; 72(2):834–836.
• Nemunaitis J, Singer JW, Buckner CD, et al. Long-term follow-up of patients who received recombinant human granulocyte-macrophage colony stimulating factor after autologous bone marrow transplantation for lymphoid malignancy. BMT 1991; 7:49–52.
• Goris RJA, Boekhorst TPA, Nuytinck JKS, et al. Multiple organ failure: Generalized auto-destructive inflammation? Arch Surg 1985; 120:1109–1115.
• Bunn P, Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the southwest oncology group. JCO 1995; 13(7):1632–1641.
• Herrmann F, Schulz G, Lindemann A, et al. Yeast-expressed granulocyte-macrophage colony-stimulating factor in cancer patients: A phase Ib clinical study. In Behring Institute Research Communications, Colony Stimulating Factors-CSF. International Symposium, Garmisch-Partenkirchen, West Germany. 1988; 83:107–118.
• Estey EH, Dixon D, Kantarjian H, et al. Treatment of poor-prognosis, newly diagnosed acute myeloid leukemia with Ara-C and recombinant human granulocytemacrophage colony-stimulating factor. Blood 1990; 75(9):1766–1769.
• Vadhan-Raj S, Keating M, LeMaistre A, et al. Effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes. NEJM 1987; 317:1545–1552.
• Buchner T, Hiddemann W, Koenigsmann M, et al. Recombinant human granulocyte-macrophage colony stimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or after relapse. Blood 1991; 78(5):1190–1197.
• Blazar BR, Kersey JH, McGlave PB, et al. In vivo administration of recombinant human granulocyte/macrophage colony-stimulating factor in acute lymphoblastic leukemia patients receiving purged autografts. Blood 1989; 73(3):849–857.

Prokine is a registered trademark licensed to Genzyme Corporation.

Manufactured by:

sanofi-aventis U.S. LLC

Bridgewater, NJ 08807

A SANOFI COMPANY

US License No. 1752

©2017 sanofi-aventis U.S. LLC

Phone: 1-888-4RX-LEUKINE

XXXXXXXX

Revised February 2017

Prokine^®

A RECOMBINANT GM-CSF -

YEAST-EXPRESSED

INFORMATION FOR PATIENTS

This patient package insert is for the injection of liquid Prokine.

IMPORTANT NOTE : Please read ALL information about Prokine in this Patient Information Leaflet before administering any injections.

This patient package insert contains information and directions for patients and their caregivers who are receiving or giving injections of Prokine at home. This package insert is intended to supplement discussions with your healthcare provider and does not take the place of talking with your doctor, nurse or pharmacist. If you have any questions about your treatment with Prokine, be sure to discuss them with your healthcare team.

Prokine ACTIONS AND USES

Prokine (loo'-kine) is the brand name of Prokine (sar-gram'-oh-stim) and is also known as granulocyte-macrophage colony-stimulating factor, or GM-CSF for short. Prokine is a man-made form of a protein, called a growth factor, that is almost identical to a protein your body makes when it is functioning normally. This growth factor helps to increase the number and function of your white blood cells, specifically neutrophils, monocytes/macrophages, and myeloid-derived dendritic cells. White blood cells, which are made in your bone marrow (the soft center of your bone), fight infections from bacteria, fungi, and viruses by surrounding and destroying them. White blood cells also help to repair tissues by removing dead and damaged cells.

If your white blood cell count (the number of white blood cells in your blood) falls to a very low level, your chance of getting an infection increases. The purpose of using Prokine is to help your bone marrow make more white blood cells, which in turn can help your immune system recover.

Prokine is used to help increase the number and function of white blood cells after bone marrow transplantation, in cases of bone marrow transplantation failure or engraftment delay, before and after peripheral blood stem cell transplantation, and following induction chemotherapy in older patients with acute myelogenous leukemia. Your doctor may also choose to treat other conditions with Prokine.

Your doctor has prescribed Prokine for you. If you are also receiving chemotherapy or radiation therapy, do not take your Prokine in the period 24 hours before through 24 hours after the administration of your chemotherapy or radiation therapy. You may also need a blood test so that your doctor can monitor your white blood cell count and, if necessary, adjust your Prokine dose.

POSSIBLE SIDE EFFECTS

Some patients taking Prokine may experience unwanted side effects, most of which are mild to moderate and not serious. Not everyone who receives Prokine will experience side effects. Some of the more common side effects include bone pain, feeling like you have the flu, feeling tired or weak, muscle aches, diarrhea, or stomach upset. You may also get a low fever (less than 100.5° F or 38° C) about one to four hours after an injection, or you may have swelling, redness, and/or discomfort where Prokine is injected. Your doctor, nurse, or pharmacist will tell you about other possible side effects. Many of these side effects can be reduced or eliminated. Talk to your doctor, nurse, or pharmacist about what you should do if any of these things happen to you.

Some side effects or symptoms may be serious. These may be due to Prokine, your illness, or other treatments you may have received. Call your doctor immediately if any of the following happen to you:

• You develop a high fever (over 100.5° F or 38° C).
• You notice any signs of infection including chills, sore throat, or congestion (such as a stuffy nose).
• You have trouble breathing, or you develop wheezing, fainting, extensive skin rash, hives, or feel you are having an allergic reaction.
• You experience sudden weight gain or other signs of fluid build-up such as swollen legs or feet.
• You develop chest pain, chest discomfort, or a rapid or irregular pulse.

If you are concerned about any other side effects or symptoms you may be having, contact your doctor, nurse, or pharmacist.

ALLERGY TO Prokine

A generalized allergy is an uncommon but potentially serious reaction to Prokine. This may include a skin rash over your entire body, hives, trouble breathing, a fast pulse, sweating, and feeling faint. In severe cases a generalized allergy may be life-threatening. If you think you are having a generalized allergy to Prokine, stop taking Prokine and notify your doctor immediately.

USAGE IN PREGNANCY AND BREAST FEEDING

If you are pregnant, are trying to become pregnant, or are breast-feeding, you should consult your doctor before taking Prokine.

STORAGE OF Prokine

Prokine should be stored in the refrigerator but not in the freezer compartment. Do not shake Prokine. Do not use Prokine that has been frozen. Keep Prokine out of direct sunlight. Do not use Prokine beyond the expiration date printed on the vial label. Once the vial has been used, any remaining Prokine should be stored in the refrigerator and used within 20 days (be sure to mark down the date you first used the vial). Throw away any remaining Prokine after 20 days.

INSTRUCTIONS FOR PREPARING AND GIVING A SELF-INJECTION

Use the correct syringe and dose

If your doctor has recommended that you take Prokine at home, your doctor, nurse, or pharmacist should have instructed you and/or your caregiver on how Prokine should be prepared, how it should be injected, and how often it should be injected.

The dose will usually be measured in milliliters (mL) or cubic centimeters (cc). (For example: 0.8 mL or 0.8 cc). It is important that you use a syringe that is marked in tenths (1/10) of a milliliter or cubic centimeter (for example: 0.1, 0.2, 0.3, 0.4, 0.5, etc... to 1.0 mL or cc) so that you are able to measure the correct dose prescribed by your doctor. A 3 cc syringe with a 25 to 30 gauge 5/8-inch needle or the syringe and needle size specified by your doctor may be used. Your doctor will either supply you with the correct syringes and needles, or will write you a prescription so you can get the correct syringes and needles from your pharmacy.

It is very important that you use the correct needle and syringe. Failure to use the correct syringe could result in your receiving either too little or too much Prokine. If you receive too little Prokine, it may not be effective. If you receive too much Prokine, your white blood cell count may get too high, which may be harmful.

Your dose has been selected to meet your individual needs. Do not change your dose without consulting your doctor. If you are not sure about the amount (mL or cc) or dose to be used, talk to your doctor, nurse, or pharmacist.

INJECTION SITE

Choosing an Injection Site

Your doctor, nurse, or pharmacist has instructed you on how to give yourself a subcutaneous (under the skin) injection of Prokine. The best areas for self-injecting Prokine are the thighs or stomach. The navel and waistline should be avoided. If a caregiver is helping with the injections, you may be instructed to inject on the back portion of the upper arms. It is a good idea to know where your injection will be given before you prepare your dose.

Rotating Injection Sites

It is important to use a different injection site each time to avoid soreness in any one area. A new injection should not be given in the same area as the last injection. It is a good idea to alternate your injection sites from one thigh to the stomach and then to the other thigh. This is called rotating your injection sites. Injection sites should be at least one inch apart. Do not choose an area where the skin is tender, bruised, red, or hard. To keep track of your injection sites, keep a record of where and when you give yourself an injection. One way to do that is to note the injection site on a calendar or in a diary along with the date you first used the vial. If all areas become tender, talk to your doctor, nurse, or pharmacist about choosing other injection sites.

Injection Site Skin Reactions

Occasionally a skin reaction may occur at the injection site. This usually will not require you to stop taking Prokine. The skin may become red, painful, or swollen. If a skin reaction occurs, contact your doctor. The following steps may be taken to help prevent further skin reactions:

• At least 30 minutes before you plan to inject, remove your Prokine from the refrigerator and allow it to come to room temperature before injecting.
• Rotate the injection sites from one injection to the next.
• Apply ice to the site for one minute immediately prior to injection.
• Inject Prokine slowly.
• Avoid rubbing the skin before or after injecting.

GIVING YOURSELF AN INJECTION

Before using Prokine for the first time, talk to your doctor, nurse, or pharmacist about how to use it, what to expect when using it, possible side effects, and what to do if side effects occur. You must be instructed and trained properly in how to prepare and inject Prokine by your doctor, nurse, or pharmacist prior to using it. Do not attempt to self-administer Prokine until you are sure that you understand the instructions for giving an injection to yourself. Your dose has been selected to meet your individual needs. Do not change your dose without consulting your doctor. If you are unsure about the amount (mL or cc) or dose to be used, how to inject yourself, or how often to inject yourself, talk to your doctor, nurse, or pharmacist.

IMPORTANT: IT IS VERY IMPORTANT THAT YOU CAREFULLY READ THESE INSTRUCTIONS AND FOLLOW THEM EXACTLY IN ORDER TO HELP AVOID CONTAMINATION OF THE Prokine AND POSSIBLE INFECTION.

Remove Prokine From the Refrigerator and Inspect the Vial and Contents

• Take the Prokine vial out of the refrigerator at least 30 minutes before you plan to inject, allowing it to come to room temperature. Do not leave the vial in direct sunlight.
• Check the date on the label to make sure the Prokine has not expired; if it has, contact your doctor, nurse, or pharmacist for further instructions. Prokine should be clear and colorless. If it is not, or if the Prokine appears to contain lumps, flakes, or particles, contact your doctor, nurse, or pharmacist.
• DO NOT SHAKE the vial. Shaking the vial could cause froth or bubbles to appear. Although this will not affect how well Prokine will work, it could decrease the amount of Prokine that you are able to draw into the syringe. If the Prokine looks frothy or bubbly, use another vial. Return the frothy or bubbly vial to the refrigerator and allow it to settle for use on another day.

Gather Your Supplies and Prepare Your Work Area

• Select a clean, convenient, well-lit location to lay out your supplies. It is a good idea to wipe down the area with an alcohol swab to make sure it is germ-free. Gather the following supplies along with the Prokine:
  • A sterile syringe and needle (as specified by your doctor, nurse, or pharmacist)
  • Prepackaged alcohol swabs
  • Ice pack
  • A puncture-resistant container for disposal of the needle and syringe
  
  

Choose and Prepare the Injection Site

• Wash your hands thoroughly with soap and warm water, and dry them with a clean towel.
  

  This should be done just before cleaning the injection site and preparing the Prokine dose.
  

• Choose an injection site. Do not choose an area where the skin is tender, bruised, red, or hard. As you have been instructed, choose a different site with each injection. Today's injection should not be given in the same area as your last injection. To keep track of your injection sites, you may want to record the injection site you picked on a calendar or in a diary. For additional information, please refer to the INJECTION SITE section above.
• Ice the site for about 1 minute before your injection. Then, with an alcohol swab, wipe the skin where the injection will be made using a gentle circular motion. Allow the skin to dry for about 10 seconds. Set the used alcohol swab aside. Do not re-use this alcohol swab.
  

Withdraw the Prokine From the Vial

• The Prokine should now be at room temperature. DO NOT SHAKE the vial.
• Flip off the plastic cap from the Prokine vial. Do not remove the gray rubber stopper.
  

• Wipe the top of the rubber stopper with a new alcohol swab. Set the used alcohol swab aside. Do not touch the rubber stopper with your hands or fingers. If you do touch the stopper, clean it again with a new alcohol swab.
  

• Remove the syringe and needle specified by your doctor from its packaging. With the cover still on the needle, draw air into the syringe by pulling back on the plunger. The amount of air you draw into the syringe should be equal to your Prokine dose.
  

• Carefully remove the needle cover. Do not lay down the syringe or allow the needle to touch anything. If the needle touches any surface, including your hands, throw away the needle and syringe in your disposal container and start over (at Step 11) with a new syringe and needle.
• With the vial upright, insert the needle downward, through the center of the gray rubber stopper. After the needle penetrates the gray rubber stopper, push the plunger all the way in to inject the air into the vial. Make sure the needle is above the Prokine. Try not to inject the air into the Prokine because bubbles may form, making it hard for you to withdraw the correct Prokine dose. The air you just injected into the vial will make it easier for you to withdraw the Prokine into the syringe. Leave the needle in the rubber stopper.
  

• Without withdrawing the needle from the rubber stopper, turn the vial upside down. Then, move the needle tip into the Prokine. Now slowly pull back on the plunger until the correct dose of Prokine is in the syringe.
  

• Before withdrawing the needle from the rubber stopper, be sure there are no air bubbles in the syringe. The air bubbles are harmless but they can decrease the amount of Prokine you receive. If there are air bubbles, gently tap the syringe with your fingers until the air bubbles rise to the top of the syringe. To remove air bubbles, gently push some of the solution back into the vial. Now slowly pull back on the plunger until the correct dose of Prokine is in the syringe. Repeat this procedure as needed until you can draw up the correct dose of Prokine without air bubbles.
• Withdraw the needle from the rubber stopper. Do not lay down the syringe or allow the needle to touch anything.

Inject the Prokine

• With one hand, gently smooth the skin of the injection site (the area you wiped with the alcohol swab) between your thumb and forefinger so it is taut.
  

• With your other hand, hold the syringe, just like a pencil, at a 90 degree angle to the skin, about 2 inches above the surface of the skin. Using a quick, short motion, insert the needle.
  

• Release your grasp on the skin. Gently pull back on the plunger just a little bit (about 1/8 of an inch). If you do not see blood in the syringe, slowly inject all of the Prokine by pushing the plunger all the way down.
  

  If you see blood in the syringe, do not inject Prokine. Withdraw the needle at the same angle it was inserted. Finding blood in the syringe simply means you hit a blood vessel rather than the fatty tissues you need to inject into, and is not a cause for concern. Discard the syringe in a puncture-resistant container. Repeat the steps to prepare a new syringe. Choose, clean, and ice a new injection site. Remember to check again for blood before injecting Prokine.
  

• Remove the needle at the same angle as it was inserted.
• Lightly touch an alcohol swab over the injection site until any bleeding has stopped. Do not rub or press the site because doing so may irritate the skin.
  

Dispose of Supplies

• It is extremely important that you do not reuse syringes or needles. Do not attempt to put the needle cover back on the needle. Throw away used syringes and needles in a puncture-resistant container as instructed by your doctor, nurse, or pharmacist. They may be able to supply you with a container made specifically for disposing of used syringes and needles. If not, then you may use the following:
  • A hard plastic container that you cannot see through with a screw-on cap, such as an empty bleach or laundry detergent bottle. Always screw the cap on tightly after disposing of your syringes and needles. Do not recycle the container.
  • A metal container with a plastic lid, such as a coffee can. Cut a hole in the plastic lid and tape the lid to the metal container
  • DO NOT use a glass or clear plastic container, or any container that will be recycled or returned to a store.
  
  

• Keep the container out of the reach of children. Make sure the container is properly labeled as to its content. When the container is about two-thirds (2/3) full, dispose of it as instructed. There may be special state and local laws regarding the proper disposal of needles and syringes that your doctor, nurse, or pharmacist may discuss with you.
• Throw away empty Prokine vials and used alcohol swabs in the trash, unless otherwise instructed.
• If the vial has any remaining Prokine, return the used vial to the refrigerator for use the next day. Do not freeze. Used vials containing Prokine should be stored in the refrigerator and used within 20 days (be sure to mark down the date you first used the vial). After 20 days, throw away any remaining Prokine.

IMPORTANT NOTES

• Follow the instructions given to you by your doctor, nurse, or pharmacist. Do not make any changes in your dose or how often you give yourself Prokine. If you are not sure about the amount (mL or cc) or dose to be used, talk to your doctor, nurse, or pharmacist.
• Try to get into a routine; give yourself Prokine at the same time each day.
• Keep Prokine and all supplies out of the reach of children.
• If any of the following happens to you, contact your doctor, nurse, or pharmacist:
  • You miss a dose of Prokine.
  • You notice anything unusual about your condition while you are taking Prokine.
  • You develop a high fever (over 100.5° F or 38° C).
  • You notice any signs of infection, including chills, sore throat, or congestion (such as a stuffy nose).

Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15

Prokine is a registered trademark licensed to Genzyme Corporation.

Manufactured by:

sanofi-aventis U.S. LLC

Bridgewater, NJ 08807

A SANOFI COMPANY

US License No. 1752

© 2016 sanofi-aventis U.S. LLC

Phone: 1-888-4RX-LEUKINE

Revised July 2016

NDC 0024-5843-05

5 × 250 mcg/vial

Prokine ^®

Prokine

A Recombinant GM-CSF–Yeast-Expressed

1.4 × 10⁶ IU/vial

Sterile

Lyophilized

Rx only

SANOFI

– 250 mcg

– 5 vials

– Injection

NDC 0024-5844-05

5 × 500 mcg/mL

Prokine ^®

Prokine

A Recombinant GM-CSF–Yeast-Expressed

2.8 × 10⁶ IU/mL

Sterile

liquid injection, contains preservative

Rx only

SANOFI

– 5 multiple

use vials

Prokine pharmaceutical active ingredients containing related brand and generic drugs:

• Sargramostim

Prokine available forms, composition, doses:

• N/A

Prokine destination | category:

• Human:
• Granulocyte macrophage colony-stimulating factor (GM-CSF) recombinant
• Immunostimulators

Prokine Anatomical Therapeutic Chemical codes:

• N/A

Prokine pharmaceutical companies:

• Sanofi-Aventis

References

1. Dailymed."LEUKINE (SARGRAMOSTIM) LIQUID LEUKINE (SARGRAMOSTIM) INJECTION, POWDER, FOR SOLUTION [SANOFI-AVENTIS U.S. LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. "Sargramostim". https://pubchem.ncbi.nlm.nih.gov/su... (accessed August 28, 2018).
3. "Sargramostim - DrugBank". http://www.drugbank.ca/drugs/DB0002... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Prokine?

Depending on the reaction of the Prokine after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Prokine not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Prokine addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

Review

sdrugs.com conducted a study on Prokine, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Prokine consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology