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Pharmacology
General: Ancestim is recombinant-methionyl human stem cell factor (r-metHuSCF), a homologue of endogenous human stem cell factor (SCF), produced by recombinant DNA technology. Hematopoietic growth factors, including SCF, are glycoproteins which act on hematopoietic cells by binding to specific cell surface receptors and stimulating proliferation, differentiation, commitment, and/or functional activation. Receptors for SCF are found on a range of early to more mature hematopoietic progenitor cells, as well as mast cells, melanocytes, and germ cells.

Endogenous SCF is a multilineage hematopoietic growth factor which is produced by bone marrow fibroblasts. In humans, the serum concentration of soluble SCF averages 3.3±1.1ng/mL.

Pharmacologic Effects of Ancestim in Combination with Neupogen (filgrastim): In phase 1/2 studies involving 367patients with breast cancer, non-Hodgkin's lymphoma, and ovarian cancer, ancestim administration over a dose range of 5to 25µg/kg/day in combination with a fixed dose of Neupogen resulted in a dose-dependent increase in circulating peripheral blood progenitor cells (PBPC) compared to Neupogen alone. The PBPCs included CD34 + cells, granulocyte macrophage colony-forming units (CFU-GM), and erythroid burst-forming units (BFU-E). For patients receiving the cytokine combination, this increase in circulating PBPC resulted in apheresis yields that were approximately 2-to 3-fold greater than those of patients receiving Neupogen alone. With discontinuation of ancestim plus Neupogen therapy, PBPC levels returned to baseline, in most cases within 4to 7days. Ancestim as a single agent did not cause substantial PBPC mobilization at the only dose tested (5µg/kg/day).

In patients receiving ancestim with Neupogen and in patients receiving Neupogen alone over the same time period, there was a similar increase in white blood cell (WBC) count. WBC levels returned to baseline with discontinuation of ancestim and Neupogen. In all studies to date, numbers of red blood cells (RBC), platelets, eosinophils, and basophils in patients receiving ancestim plus Neupogen were comparable to those in patients receiving Neupogen alone.

Pharmacokinetics: General: The pharmacokinetics of ancestim are dose-linear in the range of 5 to 30µg/kg in both healthy volunteers and cancer patients. All serum concentrations given below are corrected for endogenous SCF levels measured at baseline.

Subcutaneous Absorption: Absorption of ancestim following s.c. administration as a single agent to healthy volunteers and cancer patients is first order and is characterized by an absorption half-life of approximately 35to 41 hours following a mean lag time of 2 hours. Peak concentrations generally occur 15 to 24hours postdose (range 8to 36hours) with mean serum concentrations of 3.6, 4.9, and 13.7ng/mL following doses of 5 (n=2), 10 (n=8), and 25µg/kg (n=12) to cancer patients, similar to serum levels in healthy volunteers administered ancestim. The bioavailability in humans has not been determined since ancestim has not been administered i.v. In nonhuman primates, the bioavailability is greater than 60%.

Distribution: Studies in rats demonstrate that, after i.v. administration, ancestim distributes primarily to plasma and kidneys initially, with subsequent rapid loss from all tissues.

Metabolism: Studies in nephrectomized rats and studies of radiolabeled ancestim in normal rats demonstrated that ancestim is approximately 90% cleared by the kidney. Ancestim was not quantifiable in rat urine using ELISA, indicating degradation to lower molecular weight products.

Elimination: In healthy volunteers and in cancer patients, the half-life of elimination is 2 to 5 hours. However, absorption is the rate-limiting process so the terminal half-life is 35 to 41hours. Relative clearance is approximately 35 to 40mL/h/kg.

Multiple Dosing: Upon multiple daily dosing of ancestim in cancer patients (5, 10, 25, and 50µg/kg/day), serum levels achieve steady state after 4 or 5 days with approximately a 2-fold increase in peak concentration and area under the curve at steady state, compared to corresponding values after the first dose. There is a concomitant decrease in time to peak concentration (7 hours on day 14). When ancestim is coadministered with Neupogen, trough serum levels of ancestim increase in proportion to dose (5 to 30µg/kg/day) until approximately day 4 of dosing. Thereafter, the pharmacokinetics of ancestim are altered such that trough levels decrease due to clearance induction, despite continued administration of ancestim.

Special Populations: Children: No pediatric pharmacokinetic data are available for ancestim.

Gender: There have been no controlled comparisons of ancestim pharmacokinetic parameters in males and females, however, there were no apparent differences in these parameters between male and female lung cancer patients.

Race: There were no apparent differences in ancestim pharmacokinetic parameters between Japanese, Caucasian, and African-American subjects.

Renal Insufficiency: Based on animal studies, the kidney is the major elimination route of ancestim, and impaired renal function would be expected to cause increased serum concentrations. The clinical consequences of increased serum levels are unknown.

Drug Interactions : Over the dose ranges studied (5 to 30µg/kg/day), ancestim does not affect the pharmacokinetics of Neupogen (10to 12µg/kg/day). Neupogen alters the pharmacokinetics of ancestim as outlined above (see Multiple Dosing). It is unknown whether ancestim interacts with other drugs.

Other: At doses of 15 and 20µg/kg/day, a statistically significant increase (p=0.025) in mean trough ancestim serum levels (approximately 2ng/mL) was observed during the period of apheresis.

Indications
General: Ancestim Is Recombinant-methionyl Human Stem Cell Factor (r-metHuSCF), A Homologue Of Endogenous Human Stem Cell Factor (SCF), Produced By Recombinant DNA Technology. Hematopoietic Growth Factors, Including SCF, Are Glycoproteins Which Act On Hematopoietic Cells By Binding To Specific Cell Surface Receptors And Stimulating Proliferation, Differentiation, Commitment, And/or Functional Activation. Receptors For SCF Are Found On A Range Of Early To More Mature Hematopoietic Progenitor Cells, As Well As Mast Cells, Melanocytes, And Germ Cells.

Endogenous SCF Is A Multilineage Hematopoietic Growth Factor Which Is Produced By Bone Marrow Fibroblasts. In Humans, The Serum Concentration Of Soluble SCF Averages 3.3±1.1ng/mL.

Pharmacologic Effects Of Ancestim In Combination With Neupogen (filgrastim): In Phase 1/2 Studies Involving 367patients With Breast Cancer, Non-Hodgkin's Lymphoma, And Ovarian Cancer, Ancestim Administration Over A Dose Range Of 5to 25µg/kg/day In Combination With A Fixed Dose Of Neupogen Resulted In A Dose-dependent Increase In Circulating Peripheral Blood Progenitor Cells (PBPC) Compared To Neupogen Alone. The PBPCs Included CD34 + Cells, Granulocyte Macrophage Colony-forming Units (CFU-GM), And Erythroid Burst-forming Units (BFU-E). For Patients Receiving The Cytokine Combination, This Increase In Circulating PBPC Resulted In Apheresis Yields That Were Approximately 2-to 3-fold Greater Than Those Of Patients Receiving Neupogen Alone. With Discontinuation Of Ancestim Plus Neupogen Therapy, PBPC Levels Returned To Baseline, In Most Cases Within 4to 7days. Ancestim As A Single Agent Did Not Cause Substantial PBPC Mobilization At The Only Dose Tested (5µg/kg/day).

In Patients Receiving Ancestim With Neupogen And In Patients Receiving Neupogen Alone Over The Same Time Period, There Was A Similar Increase In White Blood Cell (WBC) Count. WBC Levels Returned To Baseline With Discontinuation Of Ancestim And Neupogen. In All Studies To Date, Numbers Of Red Blood Cells (RBC), Platelets, Eosinophils, And Basophils In Patients Receiving Ancestim Plus Neupogen Were Comparable To Those In Patients Receiving Neupogen Alone.

Pharmacokinetics: General: The Pharmacokinetics Of Ancestim Are Dose-linear In The Range Of 5 To 30µg/kg In Both Healthy Volunteers And Cancer Patients. All Serum Concentrations Given Below Are Corrected For Endogenous SCF Levels Measured At Baseline.

Subcutaneous Absorption: Absorption Of Ancestim Following S.c. Administration As A Single Agent To Healthy Volunteers And Cancer Patients Is First Order And Is Characterized By An Absorption Half-life Of Approximately 35to 41 Hours Following A Mean Lag Time Of 2 Hours. Peak Concentrations Generally Occur 15 To 24hours Postdose (range 8to 36hours) With Mean Serum Concentrations Of 3.6, 4.9, And 13.7ng/mL Following Doses Of 5 (n=2), 10 (n=8), And 25µg/kg (n=12) To Cancer Patients, Similar To Serum Levels In Healthy Volunteers Administered Ancestim. The Bioavailability In Humans Has Not Been Determined Since Ancestim Has Not Been Administered I.v. In Nonhuman Primates, The Bioavailability Is Greater Than 60%.

Distribution: Studies In Rats Demonstrate That, After I.v. Administration, Ancestim Distributes Primarily To Plasma And Kidneys Initially, With Subsequent Rapid Loss From All Tissues.

Metabolism: Studies In Nephrectomized Rats And Studies Of Radiolabeled Ancestim In Normal Rats Demonstrated That Ancestim Is Approximately 90% Cleared By The Kidney. Ancestim Was Not Quantifiable In Rat Urine Using ELISA, Indicating Degradation To Lower Molecular Weight Products.

Elimination: In Healthy Volunteers And In Cancer Patients, The Half-life Of Elimination Is 2 To 5 Hours. However, Absorption Is The Rate-limiting Process So The Terminal Half-life Is 35 To 41hours. Relative Clearance Is Approximately 35 To 40mL/h/kg.

Multiple Dosing: Upon Multiple Daily Dosing Of Ancestim In Cancer Patients (5, 10, 25, And 50µg/kg/day), Serum Levels Achieve Steady State After 4 Or 5 Days With Approximately A 2-fold Increase In Peak Concentration And Area Under The Curve At Steady State, Compared To Corresponding Values After The First Dose. There Is A Concomitant Decrease In Time To Peak Concentration (7 Hours On Day 14). When Ancestim Is Coadministered With Neupogen, Trough Serum Levels Of Ancestim Increase In Proportion To Dose (5 To 30µg/kg/day) Until Approximately Day 4 Of Dosing. Thereafter, The Pharmacokinetics Of Ancestim Are Altered Such That Trough Levels Decrease Due To Clearance Induction, Despite Continued Administration Of Ancestim.

Special Populations: Children: No Pediatric Pharmacokinetic Data Are Available For Ancestim.

Gender: There Have Been No Controlled Comparisons Of Ancestim Pharmacokinetic Parameters In Males And Females, However, There Were No Apparent Differences In These Parameters Between Male And Female Lung Cancer Patients.

Race: There Were No Apparent Differences In Ancestim Pharmacokinetic Parameters Between Japanese, Caucasian, And African-American Subjects.

Renal Insufficiency: Based On Animal Studies, The Kidney Is The Major Elimination Route Of Ancestim, And Impaired Renal Function Would Be Expected To Cause Increased Serum Concentrations. The Clinical Consequences Of Increased Serum Levels Are Unknown.

Drug Interactions : Over The Dose Ranges Studied (5 To 30µg/kg/day), Ancestim Does Not Affect The Pharmacokinetics Of Neupogen (10to 12µg/kg/day). Neupogen Alters The Pharmacokinetics Of Ancestim As Outlined Above (see Multiple Dosing). It Is Unknown Whether Ancestim Interacts With Other Drugs.

Other: At Doses Of 15 And 20µg/kg/day, A Statistically Significant Increase (p=0.025) In Mean Trough Ancestim Serum Levels (approximately 2ng/mL) Was Observed During The Period Of Apheresis.

Contraindications
In patients with known hypersensitivity to E.coli -derived proteins, ancestim, or any component of the product.

Do not administer ancestim by i.v. injection or infusion. Ancestim should only be administered by s.c. injection. Ancestim has not been administered i.v. to subjects in any clinical setting. Preclinical animal studies demonstrated increased risk of systemic allergic reactions (greater incidence and severity) when ancestim is administered by the i.v. route.

Safety Information / Warning

Ancestim should only be administered in a setting with trained medical personnel who have the appropriate medications and/or equipment necessary to treat life-threatening systemic allergic reactions if they occur. Patients should be observed for a minimum of 1 hour after administration of ancestim.

During the period of ancestim administration, all patients should be prophylactically medicated with H 1- and H 2-antihistamines and a bronchodilator to prevent or minimize the possibility of systemic allergic (i.e., anaphylactoid) reactions. Patients must be informed of the importance of taking the prescribed antihistamine and bronchodilator premedications in the period 24 hours before the first through 48hours after the last administration of ancestim (see Dosage, Premedication and Precautions, Information to Be Provided to the Patient). Patients should be instructed to immediately inform the staff if they develop symptoms of a systemic allergic reaction.

The recommended dosage must not be exceeded.

Overall, of 687 patients treated with ancestim at <30µg/kg/day (including 349at 20µg/kg/day) in clinical trials, 5% experienced systemic allergic reactions. Ten of 37 patients treated with ancestim at 30to 100µg/kg/day experienced systemic allergic events. The incidence in PBPC studies in which patients received a standard premedication regimen, and in which patients were excluded if they had a history of severe allergic disorders was 16of 516 or approximately 3% (4% in patients receiving 20µg/kg/day ancestim). These reactions have been limited to skin symptoms only (generalized urticaria) in 3 of these 16 patients. The remaining events have generally been characterized by symptoms involving at least 2body systems, most often skin (urticaria, pruritus) and respiratory (dyspnea, hoarseness, throat tightness). Angioedema and cardiovascular symptoms (tachycardia, hypotension) have also been observed. In 2patients, these reactions occurred on initial exposure. Reactions usually were somewhat delayed relative to the s.c. administration; most occurred within 12 hours after administration. Resolution of symptoms occurred after administration of additional antihistamines and/or corticosteroids. Infrequently, bronchodilators and epinephrine have been used in treating these reactions. Symptoms may recur in patients who are rechallenged, although not always on the next dose. In cases of severe reactions, rechallenge is not recommended.

In other clinical trials, there have been a few cases of severe or life-threatening systemic allergic reactions in patients treated with ancestim in which the reactions have been rapid in onset.

For the reasons stated above, patients with a history of anaphylaxis, asthma, recurrent urticaria, recurrent angioedema, or mast cell diseases (such as systemic mastocytosis, urticaria pigmentosa, or diffuse cutaneous mastocytosis) were not included in clinical trials of ancestim. It is not known whether these patients may be at increased risk of systemic allergic reactions related to ancestim administration.

Precautions
General: Ancestim should be used by physicians experienced with progenitor cell mobilization techniques. Ancestim should only be administered in a setting with trained medical personnel who have the appropriate medications and/or equipment necessary to treat life-threatening systemic allergic reactions if they occur. Patients should be observed in the hospital for a minimum of 1 hour after administration of ancestim.

Simultaneous Use with Chemo-radiotherapy: The safety and efficacy of the combination of ancestim and Neupogen (filgrastim) given simultaneously with cytotoxic chemo-radiotherapy have not been established. Because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemo-radiotherapy, it is not recommended to use ancestim in the period 24hours before through 24 hours after the administration of cytotoxic chemo-radiotherapy (see Dosage).

Leukocytosis: WBC counts of ³100´10 9/L were observed in approximately 13% of patients receiving ancestim plus Neupogen for PBPC mobilization, compared with 1% of patients receiving Neupogen alone. Most of these occurred when cytokine administration exceeded 7days. There were no reports of adverse events associated with this degree of leukocytosis and counts decreased rapidly with cessation of Neupogen administration.

Laboratory Monitoring: Platelet counts were generally within normal limits prior to ancestim plus Neupogen therapy. With ancestim plus Neupogen therapy for PBPC mobilization, platelet counts were generally stable prior to apheresis, but, as expected, decreased during the apheresis procedures in patients receiving Neupogen alone or ancestim plus Neupogen.

In some trials of ancestim in combination with Neupogen, there were increases in serum uric acid, lactate dehydrogenase, and serum alkaline phosphatase beyond those observed with Neupogen alone. No clinical events related to these increases have been reported.

Drug Interactions : Drug interactions between ancestim and other drugs (including cytokines other than Neupogen) have not been fully evaluated. The potential for interaction with drugs, such as radiocontrast agents, which may potentiate the release of histamine or other mast cell mediators, is unknown.

Growth Factor Potential: Ancestim is a growth factor that stimulates hematopoietic progenitor cells, mast cells, and melanocytes. Stimulation of small cell lung carcinoma cell lines and acute myelogenous leukemia cells has also been observed in vitro in some studies. Although ancestim is intended to be administered prior to high-dose chemo-radiotherapy, the possibility that ancestim can act as a growth factor for any tumor type, particularly myeloid malignancies, melanomas, small cell lung cancers, and basophilic or mast cell leukemias cannot be excluded. Therefore, precaution should be exercised in using ancestim in these diseases.

When ancestim is used with Neupogen to mobilize PBPC, tumor cells may be collected in the apheresis product. The effect of re-infusion of tumor cells has not been well-studied, and the limited data available are inconclusive. The phase3 trial found no difference in the incidence of breast cancer contamination in apheresis products from patients mobilized with ancestim in combination with Neupogen (3% of patients), compared to those from patients mobilized with Neupogen alone (5% of patients).

Carcinogenesis, Mutagenesis: The carcinogenic potential of ancestim has not been studied. Ancestim failed to induce bacterial gene mutations in either the presence or absence of a drug metabolizing enzyme system. Similarly, ancestim did not increase the incidence of chromosomal abnormalities or micronuclei in bone marrow or peripheral blood erythrocytes in mice.

Impairment of Fertility: Ancestim had no observed effect on the fertility of male monkeys at doses up to 500µg/kg nor on the fertility of female monkeys, nor on gestation, at doses up to 1000µg/kg.

Pregnancy: Reproduction studies have been performed in monkeys at doses up to 50 times the recommended human dose and have revealed no evidence of impaired fertility or harm to the fetus due to ancestim. There are, however, no adequate and well-controlled studies in pregnant women. Animal reproduction studies are not always predictive of human response, therefore caution should be exercised if ancestim is administered during pregnancy.

Lactation: It is not known whether ancestim is excreted in human milk. Many drugs are excreted in human milk, therefore caution should be exercised if ancestim is administered to a nursing woman.

Children: The safety and efficacy of ancestim in pediatric cancer patients have not been established. At least 7patients under age12 have been treated with ancestim, with or without Neupogen, in clinical trials of patients with bone marrow failure syndromes. There has been no apparent increase in the incidence or severity of adverse events in premedicated pediatric patients.

Geriatric: Clinical studies of ancestim did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. At least 9geriatric cancer patients have been treated with ancestim in clinical trials. There has been no apparent increase in the incidence or severity of adverse events in premedicated geriatric patients.

Information to Be Provided to the Patient: Patients must be informed of the importance of taking the prescribed antihistamine and bronchodilator premedications in the period 24hours before the first, through 48hours after the last administration of ancestim. Patients should be instructed to immediately inform the staff if they develop symptoms of a systemic allergic reaction. If a reaction occurs when a patient has left the hospital they should be informed to contact their physician immediately. If the reaction is very severe and the patient is having difficulty breathing or swallowing, they should be instructed to contact emergency medical personnel immediately. Because of the possibility of allergic reactions patients should be instructed to keep their premedications with them at all times.

Overdose
Symptoms and Treatment: The maximum tolerated dose of ancestim, when administered with premedications, has not been determined; however, the incidence of systemic allergic reactions appears to be dose-related.

Overall, of 687 patients treated with ancestim at <30µg/kg/day (including 349 at 20µg/kg/day) in clinical trials, 5% experienced systemic allergic reactions. Ten of 37 patients treated with ancestim at 30 to 100µg/kg/day experienced systemic allergic reactions.

Recommended Dosage
The recommended dose for use in combination with Neupogen (filgrastim) for the mobilization of PBPC, is 20µg/kg/day as a s.c. injection. For the correct use of Neupogen, please refer to the Neupogen product monograph. Ancestim should not be administered without Neupogen. However, ancestim and Neupogen must be administered as separate injections, at different sites. Ancestim should not be used at doses above the recommended dose.

In cytokine-alone mobilization regimens, daily administration of ancestim plus Neupogen with daily aphereses beginning on day5 was found to be safe and effective. WBC counts should be monitored after 4 days of ancestim plus Neupogen, and Neupogen dose-modification should be considered for those patients who develop a WBC count >100´10 9/L.

In chemotherapy-based mobilization regimens, daily ancestim plus Neupogen should be initiated 24hours after the administration of cytotoxic chemotherapy. Beginning aphereses on the day the WBC count rises through 4´10 9/L has been shown to be effective in clinical trials.

Ancestim should not be administered i.v. (see Contraindications). No information is available on continuous s.c. infusion of ancestim. Ancestim should only be administered by s.c. injection and must be reconstituted with 1.2mL Sterile Water for Injection, USP (see Reconstitution and Dilution below).

Ancestim should only be administered in a setting with trained medical personnel who have the appropriate medications and/or equipment necessary to treat life-threatening systemic allergic reactions if they occur. Ancestim should not be self-administered.

Premedication: Patients receiving ancestim must be premedicated with H 1- and H 2-antihistamines and a bronchodilator (b-agonist). In clinical trials, either diphenhydramine (50 mg orally, every 6hours) or cetirizine (10 mg orally, once daily) was used most frequently as the H 1-antihistamine, ranitidine (150 mg orally, every 12hours or 300 mg orally, once daily) was the most commonly used H 2 antihistamine, and salbutamol inhaler (2 puffs, 30 to 60minutes prior to each injection) was used as the bronchodilator. Administration of H 1- and H 2-antihistamines should start 12 to 24hours prior to the first injection of ancestim. Further administration should be timed such that a dose is given 60 to 90 minutes prior to each ancestim injection, and should continue until 48 hours after the last injection.

Reconstitution and Dilution: Stemgen must be reconstituted with 1.2mL Sterile Water for Injection, USP (without preservative) to yield an ancestim concentration of 1500µg/mL with a withdrawable volume of 1.0mL. Compatibility with saline or other diluents is unknown. During reconstitution, the vial contents may be gently swirled to avoid foaming during dissolution. Avoid excess or vigorous agitation; do not shake.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration; if particulates or discoloration are observed, the contents of the container should not be used.

Stability and Storage: Stemgen as a sterile powder should be stored in the refrigerator at 2to 8°C. Do not freeze. Any vial of powder left at room temperature for more than 72hours should be discarded. Do not use after the expiry date.

Stemgen should be used immediately after reconstitution; although not recommended, the product may be used up to 24hours after reconstitution when stored at 2to 8°C. Avoid shaking. Prior to injection, reconstituted solution may be allowed to reach room temperature.

Use only 1dose per reconstituted vial; do not re-enter the vial. Discard unused portions. Do not save unused drug for later administration.

Information for the Patient: See Blue Section--Information for the Patient “Stemgen”.

Supplied / Packaging
Stemgen is a 166 amino acid protein produced by E.coli bacteria into which a gene has been inserted for soluble human stem cell factor. Stemgen normally exists as a noncovalently associated dimer. The theoretical molecular weight of the monomer is 18657 daltons. The protein has an amino acid sequence that is identical to the natural sequence predicted from human DNA sequence analysis, except for the addition of an N-terminal methionine retained after expression in E. coli . Stemgen is produced in E.coli and therefore is nonglycosylated. The molecular formula of the Stemgen monomer is C 831H 1325N 211O 256S 9, the formula fornonreduced noncovalently-linked dimer is exactly double (C 1662H 2650N 422O 512S 18). The specific activity (as measured by a cell mitogenesis assay) is 0.84 to 1.8´10 6U/mg.

Each vial of sterile, lyophilized powder formulation contains: ancestim 1875µg. Nonmedicinal ingredients: glutamic acid, histidine, mannitol and sucrose. Preservative-free. Single-use vials. Sterile water for injection USP diluent is provided with the lyophilized powder. Dispensing packages of 3vials of Stemgen and 3vials of sterile water for injection diluent. Should be stored in the refrigerator at 2to 8°C. Do not freeze. Discard any vial of powder left at room temperature for more than 72hours. Do not use after expiry date.