ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Myelosuppression [see Warnings and Precautions 5.1)] Seizures [see Warnings and Precautions 5.2)] Skin Disorders [see Warnings and Precautions 5.3)] Injection Site Reactions and Tissue Necrosis [see Warnings and Precautions 5.4)] Secondary Malignancies [see Warnings and Precautions 5.5)] Myelosuppression [see Warnings and Precautions 5.1)] Seizures [see Warnings and Precautions 5.2)] Skin Disorders [see Warnings and Precautions 5.3)] Injection Site Reactions and Tissue Necrosis [see Warnings and Precautions 5.4)] Secondary Malignancies [see Warnings and Precautions 5.5)] The most common adverse reactions (>=20%) are musculoskeletal pain, stomatitis, pyrexia, nausea, edema, infection, and vomiting. 6.1) Selected Grade or nonhematological laboratory abnormalities are increased GGT, increased bilirubin, increased ALT, increased AST, and increased creatinine. To report SUSPECTED ADVERSE REACTIONS, contact Medexus Pharma, Inc. at 1-855-336 -3322 or FDA at 1-800-FDA-1088 orwww.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.MC-FludT.14/L Trial IIThe safety of GRAFAPEX was evaluated in 553 adult patients with AML and MDS in randomized trial (MC-FludT.14/L Trial II) comparing GRAFAPEX in combination with fludarabine to busulfan in combination with fludarabine as preparative regimen for allogeneic hematopoietic stem cell transplantation. The patients were randomized to receive GRAFAPEX (n=270) 10 g/m2 daily on day -4, -3 and -2 or to busulfan (n=283) 0.8 mg/kg every hours on day -4 and -3 in combination with fludarabine 30 mg/m 2daily on day -6, -5, -4, -3 and -2, and hematopoietic stem cell transplantation on day [see Clinical Studies 14)] Fatal regimen-related adverse reactions occurred within 30 days of transplantation in 1.9% of patients on the GRAFAPEX arm. All fatalities were due to pulmonary adverse reactions.The most common adverse reactions (>=20%) in patients treated with GRAFAPEX were musculoskeletal pain, stomatitis, pyrexia, nausea, edema, infection, and vomiting. Selected Grade or nonhematological laboratory abnormalities were increased GGT, increased bilirubin, increased ALT, increased AST, and increased creatinine. Table shows the adverse reactions in Study MC-FludT.14/L Trial II through transplant Day +30.Table 3: Adverse Reactions in >=10% of Patients through Transplant Day +30 in Study MC-FludT.14/L Trial II Adverse ReactionAll GradesGrades or 4GRAFAPEX(N 270)Busulfan(N 283)GRAFAPEX(N 270)Busulfan(N 283) % % Musculoskeletal pain 39 27 2 Stomatitis 38 48 7 Pyrexia 34 36 3 Nausea 33 41 6 Edema 29 18 0.7 Infection 23 18 12 Vomiting 22 19 1 Rash 17 13 1 Diarrhea 17 18 1 Headache 16 18 1 Febrile neutropenia 15 11 15 11 Abdominal pain 15 13 2 Hypertension 14 21 10 Hemorrhage 14 14 1 Fatigue 13 15 0.4 Constipation 12 12 0.4 Tachycardia 10 1 Hepatotoxicity 10 4 3Includes grouped terms 1Includes fatalities: n=6 in the GRAFAPEX arm and n=2 in the busulfan arm Grading is based on Common Terminology Criteria for Adverse Events version 4.03 Clinically relevant adverse reactions in <10% of patients who received GRAFAPEX included:Neoplasms benign, malignant and unspecified (including cysts and polyps): second malignancy Metabolism and nutrition disorders: Decreased appetite, impaired glucose tolerance Psychiatric disorders: Insomnia, confusional state, agitation Nervous system disorders: Paresthesia, dizziness Ear and labyrinth disorders: Vertigo Cardiac disorders: Cardiac failure, pericardial effusion Vascular disorders: Flushing, embolism, hypotension Respiratory, thoracic and mediastinal disorders: Pneumonitis, pleural effusion, pharyngeal or laryngeal inflammation, dyspnea, cough, oropharyngeal pain, hiccups, dysphonia Gastrointestinal disorders: Oral pain, gastritis, dyspepsia, dysphagia, abdominal distension, dry mouth Skin and subcutaneous tissue disorders: Palmar plantar erythrodysesthesia syndrome, pruritus, erythema, dermatitis, skin hyperpigmentation, dry skin Renal and urinary disorders: Acute kidney injury, hematuria, urinary tract pain General disorders and administration site conditions: Chills, pain Investigations: Weight decreased or increased, increase of C-reactive proteinAll patients treated with GRAFAPEX and fludarabine developed neutropenia, anemia, and thrombocytopenia. One patient on the GRAFAPEX arm had graft failure. Table summarizes the selected nonhematological laboratory abnormalities in Study MC-FludT.14/L Trial II by treatment arm through Day +30 posttransplant.Table 4. Selected Grades 3-4 Laboratory Abnormalities through Transplant Day +30 in Study MC-FludT.14/L Trial IILaboratory AbnormalityGRAFAPEX = 270 %Busulfan = 283 %Gamma Glutamyl Transferase Increased1628Bilirubin Increased65Alanine Aminotransferase Increased64Aspartate Aminotransferase Increased41Creatinine Increased30.7Grading is based on Common Terminology Criteria for Adverse Events version 4.03. 6.2 Postmarketing Experience. The following additional adverse reactions have been identified during post approval use of GRAFAPEX in preparative regimens prior to hematopoietic stem cell transplantation in adult and pediatric patients in other countries. As these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Metabolism and Nutrition Disorders: Acidosis Nervous system disorders: Peripheral sensory neuropathy Renal and urinary disorders: Renal failure Immune system disorders: Hypersensitivity.

BOXED WARNING SECTION.

WARNING: MYELOSUPPRESSION. GRAFAPEX causes severe and prolonged myelosuppression at the recommended dosage.Hematopoietic stem cell transplantation is required to prevent potentially fatal complications of the prolonged myelosuppression. Monitor hematologic laboratory parameters[see Warnings and Precautions 5.1)] . GRAFAPEX causes severe and prolonged myelosuppression at the recommended dosage.. Hematopoietic stem cell transplantation is required to prevent potentially fatal complications of the prolonged myelosuppression. Monitor hematologic laboratory parameters[see Warnings and Precautions 5.1)] . WARNING: MYELOSUPPRESSIONSee full prescribing information for complete boxed warning.GRAFAPEX causes severe and prolonged myelosuppression.Hematopoietic stem cell transplantation is required to prevent potentially fatal complications of the prolonged myelosuppression. Monitor hematologic laboratory parameters. 5.1 ). GRAFAPEX causes severe and prolonged myelosuppression.. Hematopoietic stem cell transplantation is required to prevent potentially fatal complications of the prolonged myelosuppression. Monitor hematologic laboratory parameters. 5.1 ).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. GRAFAPEX is an alkylating drug indicated for:Use in combination with fludarabine as preparative regimen for allogeneic hematopoietic stem cell transplantation (alloHSCT) in adult and pediatric patients year of age and older with acute myeloid leukemia (AML). 1.1). Use in combination with fludarabine as preparative regimen for allogeneic hematopoietic stem cell transplantation in adult and pediatric patients year of age and older with myelodysplastic syndrome (MDS). 1.2). Use in combination with fludarabine as preparative regimen for allogeneic hematopoietic stem cell transplantation (alloHSCT) in adult and pediatric patients year of age and older with acute myeloid leukemia (AML). 1.1). Use in combination with fludarabine as preparative regimen for allogeneic hematopoietic stem cell transplantation in adult and pediatric patients year of age and older with myelodysplastic syndrome (MDS). 1.2). 1.1 Acute Myeloid Leukemia. GRAFAPEX is indicated in combination with fludarabine as preparative regimen for allogeneic hematopoietic stem cell transplantation in adult and pediatric patients year of age and older with acute myeloid leukemia (AML).. 1.2 Myelodysplastic Syndrome. GRAFAPEX is indicated in combination with fludarabine as preparative regimen for allogeneic hematopoietic stem cell transplantation in adult and pediatric patients year of age and older with myelodysplastic syndrome (MDS).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Treosulfan is an alkylating agent. DNA alkylation is thought to be responsible for the cytotoxic activities of treosulfan. Treosulfan showed hematopoietic stem cell depleting activity as well as immunosuppressive and antitumor activity in mouse models of leukemia.. 12.2 Pharmacodynamics. Increase in treosulfan exposure was associated with an increased incidence of infection-related death. Treosulfan time course of pharmacodynamic response is unknown.. 12.3 Pharmacokinetics. Treosulfan pharmacokinetic parameters were observed at the approved recommended dosage, unless otherwise specified.Treosulfan is prodrug. Treosulfan mean +- SD area under the curve (AUC) is 1,200 +- 211 hr mcg/mL. There was no dose accumulation.DistributionTreosulfan mean (CV%) volume of distribution is approximately 41 liters (CV%: 19%). Treosulfan does not bind to plasma albumin.EliminationTreosulfan mean (+- standard deviation) terminal half-life is 1.7 +- 0.4 hours.MetabolismThe pharmacologically inactive treosulfan is converted spontaneously under physiological conditions into the active monoepoxide intermediate (2S,3S)-1,2-epoxybutane-3,4-diol-4-methanesulfonate) and finally to active L-diepoxibutane (2S,3S)-1,2:3,4-diepoxybutane).ExcretionA median of 42% of the treosulfan dose is excreted unchanged in the urine within 24 hours, and 89% of this unchanged fraction is excreted within the first hours after administration.Specific PopulationsNo clinically significant differences in the pharmacokinetics of treosulfan based on sex, mild renal impairment (CLcr 60-89 mL/min), or mild hepatic impairment (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than to 1.5 times ULN with any AST). The effect of moderate or severe renal impairment, moderate or severe hepatic impairment, and age >= 65 years on treosulfan pharmacokinetics is unknown.Pediatric PatientsTreosulfan exposure in pediatric patients with BSA 0.7 2and with BSA 0.7 to 1.1 2are 11% and 5% higher, respectively, compared to adults. No clinically significant difference in treosulfan median terminal half-life was observed between pediatric patients and adults. The median terminal half-life of the active monoepoxide intermediate was 1.6 hrs in pediatric patients.Drug Interaction StudiesIn Vitro StudiesCYP Enzymes:Treosulfan is CYP2D6 substrate and its monoepoxide intermediate is CYP2C8 substrate. Treosulfan inhibits CYP2C19 and CYP3A4 (using midazolam as substrate), but does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, or CYP3A4 (using testosterone as substrate). Transporter Systems: Treosulfan does not inhibit BCRP, BSEP, MATE1, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, or OCT2.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of GRAFAPEX was evaluated in randomized active-controlled trial (MC-FludT.14/L Trial II; NCT00822393) comparing GRAFAPEX to busulfan in combination with fludarabine as preparative regimen for allogeneic transplantation. Eligible patients included adults 18 to 70 years old with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), Karnofsky performance status 60%, and age >= 50 years or hematopoietic cell transplantation comorbidity index [HCT-CI] score 2. Patients were excluded if the creatinine clearance was 60 mL/min, forced expiratory volume (FEV1) 50% or on supplemental oxygen, left ventricular ejection fraction (LVEF) 40%, bilirubin 3X ULN, or aminotransferases (ALT or AST) 5X ULN. The patients were randomized to receive GRAFAPEX 10 g/m2 daily on day -4, -3 and -2 or to busulfan 0.8 mg/kg every hours on day -4 and -3 in combination with fludarabine 30 mg/m 2daily on day -6, -5, -4, -3 and -2, and hematopoietic stem cell transplantation on day 0. For the subset of patients with unrelated donors, antithymocyte globulin was administered in 97% and 95% of patients on each arm, respectively. Cyclosporine and methotrexate was used as graft-vs-host disease prophylaxis. There were 570 patients randomized to GRAFAPEX (n 280) or busulfan (n 290). The efficacy population included 365 patients with AML and 205 patients with MDS: 536 patients received peripheral blood stem cells, 15 patients received marrow stem cells, and 19 patients were not transplanted. Table shows the baseline characteristics of the study patients. Table 5: Baseline characteristics of the study patients (MC-FludT.14/L Trial II)Baseline CharacteristicsGRAFAPEX (n 280)Busulfan (n 290)Age, median (range), years60.0 (37, 70)60.5 (31, 70)Age, (%)18-64 years65-70 years 204 (73%) 76 (27%)218 (75%)72 (25%)Gender, (%)MaleFemale171 (61%) 109 (39%) 176 (61%) 114 (39%) Weight, median (range), kg80.0 (48.0, 144.0)78.1 (46.0, 141.9)Disease, (%) AML MDS192 (69%)88 (31%)173 (60%)117 (40%)AML remission status, (%)CR1>CR1164 (85%)28 (15%) 148 (86%)25 (14%) MDS risk group, (%) Lower riskHigher risk 20 (23%)68 (77%) 20 (17%)97 (83%) HCT-CI score<=2>2116 (41%)164 (59%) 118 (41%)172 (59%) DonorMatched relatedMatched unrelated66 (24%)214 (76%) 68 (23%)222 (77%) Abbreviations: AML: acute myeloid leukemia; MDS: myelodysplastic syndrome; CR1: complete remission 1; HCT-CI: hematopoietic cell transplant-specific comorbidity indexEfficacy was established on the basis of overall survival (OS), defined as the time from randomization until death from any cause. The hazard ratio (HR) for OS (stratified by donor type and risk group) compared to busulfan was 0.67 (95% CI: 0.51, 0.90) in the randomized population, 0.73 (95% CI: 0.51, 1.06) in patients with AML, and 0.64 (95% CI: 0.40, 1.02) in patients with MDS. Results are displayed in Figures 1, 2, and below.Figure 1: Kaplan-Meier estimates of overall survival since time of randomization MC FludT.14/L Trial IIFigure 2: Kaplan-Meier estimates of overall survival since time of randomization MC FludT.14/L Trial II (patients with AML)Figure 3: Kaplan-Meier estimates of overall survival since time of randomization MC FludT.14/L Trial II (patients with MDS). 18-64 years. 65-70 years. Male. Female. CR1. >CR1. Lower risk. Higher risk. <=2. >2. Matched related. Matched unrelated. Figure 1. Figure 2. Figure 3.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended dosage: 10 g/m2 body surface area (BSA) per day as two hour intravenous infusion, given on three consecutive days (day -4, -3, -2) in conjunction with fludarabine before hematopoietic stem cell infusion (day 0). 2.1, 2.2) See Full Prescribing Information for instructions on preparation and administration. 2.2) See Full Prescribing Information for instructions on preparation and administration. 2.2) 2.1 Recommended Dosage. The recommended dosage of GRAFAPEX is 10 g/m 2by intravenous infusion given daily for three days, beginning on Day -4 prior to transplantation in combination with fludarabine as outlined in Table 1. Table 1: Dosage Regimen for GRAFAPEX-Based Allogeneic HSCTTreatmentDay -6Day -5Day -4 Day-3Day -2Day -1Day 0GRAFAPEX 10 g/m 2/day intravenous infusion XXXFludarabine 30 mg/m 2/day intravenous infusion XXXXXAllogeneic hematopoietic stem cell infusionXPremedicate patients with antiemetics prior to the first dose of GRAFAPEX and continue antiemetics on fixed schedule through completion of treosulfan administration.. 2.2 Preparation and Administration Instructions. Reconstitute GRAFAPEX prior to intravenous infusion.GRAFAPEX is hazardous drug. Follow applicable special handling and disposal procedures. Use aseptic technique to prepare GRAFAPEX.Calculate the dose, the total volume of reconstituted GRAFAPEX solution required, and the number of GRAFAPEX vials needed.Reconstitute each vial with 0.45% Sodium Chloride Injection, 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or Sterile Water for Injection, in its original glass container using volumes described in Table to obtain final concentration of approximately 0.05 g/mL of GRAFAPEX. Reconstitution with Sterile Water for Injection alone is not recommended in children less than or equal to 12 years of age due to the resulting hypo-osmolarity of the final solution.Table 2: Reconstitution Solution VolumeStrengthVolume1 g/vial20 mL5 g/vial100 mLShake the vial(s) to dissolve.Inspect the reconstituted solution for discoloration and particulate matter. The reconstituted solution appears as clear colorless solution. Solutions showing any sign of precipitation should not be used. In case that solubility issues occur, prolonged standing time or slight warming of the reconstituted solution (hand warm) may be useful.Determine the volume of 0.05 g/mL reconstituted solution needed based on the required dose. Reconstituted solutions of GRAFAPEX may be combined into larger glass vial, ethylene-vinyl acetate (EVA) bag or polyolefin (PO) bag. Discard any unused portion left in the vial(s).If not used immediately store reconstituted GRAFAPEX solution at room temperature 20C to 25C (68F to 77F) for up to 24 hours. Do not use if the solution contains precipitate.Do not refrigerate.Infuse GRAFAPEX intravenously over hours. Confirm patency of the intravenous line prior to infusion. Monitor for extravasation; if extravasation occurs, stop the infusion [see Warnings and Precautions 5.4)] . Use aseptic technique to prepare GRAFAPEX.. Calculate the dose, the total volume of reconstituted GRAFAPEX solution required, and the number of GRAFAPEX vials needed.. Reconstitute each vial with 0.45% Sodium Chloride Injection, 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or Sterile Water for Injection, in its original glass container using volumes described in Table to obtain final concentration of approximately 0.05 g/mL of GRAFAPEX. Reconstitution with Sterile Water for Injection alone is not recommended in children less than or equal to 12 years of age due to the resulting hypo-osmolarity of the final solution.. Shake the vial(s) to dissolve.. Inspect the reconstituted solution for discoloration and particulate matter. The reconstituted solution appears as clear colorless solution. Solutions showing any sign of precipitation should not be used. In case that solubility issues occur, prolonged standing time or slight warming of the reconstituted solution (hand warm) may be useful.. Determine the volume of 0.05 g/mL reconstituted solution needed based on the required dose. Reconstituted solutions of GRAFAPEX may be combined into larger glass vial, ethylene-vinyl acetate (EVA) bag or polyolefin (PO) bag. Discard any unused portion left in the vial(s).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. InfectionsInform patients of the increased risk of infections after treatment with GRAFAPEX that may require antibiotic, antiviral, or antifungal treatment and hospitalization.Advise patients to contact their healthcare provider immediately in case of any new or worsening signs of infection, e.g., cough, headache, diarrhea, or fever [see Warnings and Precautions 5.1)] SeizuresInform patients that seizures may occur see Warnings and Precautions 5.2)] Skin DisordersAdvise patients to clean sweaty skin parts (armpit, groin, genital area, inframammary line), each with disposable washcloth and clear water.Advise patients not to apply any cream to the skin on the days of chemotherapy, and clothing should not be too tight, in order to let the skin breathe [see Warnings and Precautions 5.3)] Secondary MalignanciesInform patients of the possible risk of second malignancy [see Warnings and Precautions 5.5)] Embryo-Fetal ToxicityAdvise females of reproductive potential of the potential risk to fetus and to inform their healthcare provider of known or suspected pregnancy [see Use in Specific Populations 8.1)] Advise females of reproductive potential to use effective contraception during treatment with GRAFAPEX and for months following the last dose of GRAFAPEX [see Warnings and Precautions 5.7) and Use in Specific Populations 8.3)] Advise males with female partners of reproductive potential to use effective contraception during treatment with GRAFAPEX and for months after the last dose [see Warnings and Precautions 5.7) and Use in Specific Populations 8.3)] LactationAdvise women not to breastfeed during treatment with GRAFAPEX and for week after the last dose [see Use in Specific Populations 8.2)]. InfertilityGRAFAPEX can impair fertility in females and males, and may cause temporary or permanent infertility [see Use in Specific Populations 8.3)] Manufactured for: Medexus Pharma, Inc. Chicago, Illinois 60606 USA GRAFAPEX(TM) is trademark of medac GmbH, Germany.. Inform patients of the increased risk of infections after treatment with GRAFAPEX that may require antibiotic, antiviral, or antifungal treatment and hospitalization.. Advise patients to contact their healthcare provider immediately in case of any new or worsening signs of infection, e.g., cough, headache, diarrhea, or fever [see Warnings and Precautions 5.1)] . Inform patients that seizures may occur see Warnings and Precautions 5.2)] . Advise patients to clean sweaty skin parts (armpit, groin, genital area, inframammary line), each with disposable washcloth and clear water.. Advise patients not to apply any cream to the skin on the days of chemotherapy, and clothing should not be too tight, in order to let the skin breathe [see Warnings and Precautions 5.3)] . Inform patients of the possible risk of second malignancy [see Warnings and Precautions 5.5)] . Advise females of reproductive potential of the potential risk to fetus and to inform their healthcare provider of known or suspected pregnancy [see Use in Specific Populations 8.1)] . Advise females of reproductive potential to use effective contraception during treatment with GRAFAPEX and for months following the last dose of GRAFAPEX [see Warnings and Precautions 5.7) and Use in Specific Populations 8.3)] . Advise males with female partners of reproductive potential to use effective contraception during treatment with GRAFAPEX and for months after the last dose [see Warnings and Precautions 5.7) and Use in Specific Populations 8.3)] . Advise women not to breastfeed during treatment with GRAFAPEX and for week after the last dose [see Use in Specific Populations 8.2)]. GRAFAPEX can impair fertility in females and males, and may cause temporary or permanent infertility [see Use in Specific Populations 8.3)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. 8.2) Lactation: Advise not to breastfeed. 8.2) 8.1 Pregnancy. Risk SummaryBased on its mechanism of action, GRAFAPEX can cause fetal harm when administered to pregnant woman because it is genotoxic and affects dividing cells [see Clinical Pharmacology 12) and Nonclinical Toxicology 13)] There are no available human clinical data on the use of treosulfan in pregnant women to support an estimation of drug-associated risk. Specific embryo-fetal developmental toxicity studies with treosulfan in animals were not conducted. Advise pregnant women of the potential risk to fetus [see Data]. In the U.S. general population, the estimated background risk of major birth defects is 2% 4% and of miscarriage is 15% 20% of clinically recognized pregnancies.DataAnimal DataAnimal reproductive or developmental toxicity studies were not conducted with treosulfan. Treosulfan is genotoxic and is toxic to dividing cells, suggesting it can cause embryotoxicity and teratogenicity.. 8.2 Lactation. Risk SummaryThere is no data on the presence of treosulfan or its metabolites in human milk, the effects on the breastfed child, or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with GRAFAPEX and for week after the last dose.. 8.3 Females and Males of Reproductive Potential. Based on its mechanism of action, GRAFAPEX can cause fetal harm when administered to pregnant woman [see Use in Specific Populations 8.1)]. Pregnancy TestingConduct pregnancy testing in females of reproductive potential within days prior to initiating therapy with GRAFAPEX.ContraceptionFemalesAdvise females of reproductive potential to use effective contraception during and up to months after treatment with GRAFAPEX.MalesBecause of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with GRAFAPEX and for months after the last dose [see Nonclinical Toxicology 13.1)] InfertilityBased on findings in animal studies, GRAFAPEX can impair fertility in females and males, and may cause temporary or permanent infertility [see Nonclinical Toxicology 13.1)] . 8.4 Pediatric Use. The safety and efficacy of GRAFAPEX as part of preparative regimen prior to allogeneic hematopoietic stem cell transplant in pediatric patients year of age and older with AML or MDS have been established based on evidence from an adequate and well-controlled study in adults, with additional pharmacokinetic and safety data in 111 pediatric patients, including 22 infants (1 month to 2 years), 54 children (2 to 12 years), and 35 adolescents (12 to 17 years) [see Adverse Reactions 6.1), Clinical Pharmacology 12.3), and Clinical Studies 14)] The incidence of hepatic and gastrointestinal adverse reactions was higher in pediatric patients than in adults. Safety and effectiveness of GRAFAPEX as part of preparative regimen prior to allogeneic hematopoietic stem cell transplant in pediatric patients with AML or MDS younger than year of age have not been established.Juvenile Animal Toxicity DataTreatment of juvenile rats from postnatal day (PND) 10 to 35 with daily doses of 10, 50 or 100 mg/kg treosulfan (approximately 0.006, 0.03, 0.06--fold the human dose based on body surface area, BSA) generally resulted in findings comparable to those seen in adult animals. delayed physical development indicated by decreased body weight, reduced relative organs weights, and delayed time point of vaginal opening were noted in the high-dosed rats. In separate study, single intravenous administrations of 500 mg/kg treosulfan (0.3--fold the human dose based on BSA) to juvenile (PND 10) and young adult (PND 34 35) rats, treosulfan concentrations in brain tissue were low compared to plasma concentrations, but were approximately 2- to 3-fold higher in juvenile rats (4-6%) in comparison to young adults (2-3%).. 8.5 Geriatric Use. Of the total number of GRAFAPEX-treated patients with AML or MDS in Study MC-FludT.14/L Trial II (n=270), 73 (27%) were 65 to 74 years of age, and none were 75 years of age and older [see Clinical Studies 14)] No significant differences in safety or effectiveness were observed between these subjects and younger subjects.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Seizures: Monitor signs of neurological adverse reactions and consider clonazepam prophylaxis for patients at higher risk. 5.2) Skin disorders: Keep skin clean and dry on days of GRAFAPEX infusion and change occlusive dressings after infusion. Change diapers frequently during the 12 hours after each infusion of GRAFAPEX. 5.3) Injection Site Reactions and Tissue Necrosis: May cause local tissue necrosis and injection site reactions, including erythema, pain, and swelling, in case of extravasation. If extravasation occurs, stop the infusion immediately and manage medically as required. 5.4) Secondary Malignancies: There is an increased risk of secondary malignancy with use of GRAFAPEX. 5.5) Increased Early Morbidity and Mortality at Dosages Higher than Recommended: Avoid exceeding the recommended dosage of 10 g/m 2daily for three consecutive days. 5.6) Embryo-fetal toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to fetus and to use effective contraception. 5.7, 8.1, 8.3) Seizures: Monitor signs of neurological adverse reactions and consider clonazepam prophylaxis for patients at higher risk. 5.2) Skin disorders: Keep skin clean and dry on days of GRAFAPEX infusion and change occlusive dressings after infusion. Change diapers frequently during the 12 hours after each infusion of GRAFAPEX. 5.3) Injection Site Reactions and Tissue Necrosis: May cause local tissue necrosis and injection site reactions, including erythema, pain, and swelling, in case of extravasation. If extravasation occurs, stop the infusion immediately and manage medically as required. 5.4) Secondary Malignancies: There is an increased risk of secondary malignancy with use of GRAFAPEX. 5.5) Increased Early Morbidity and Mortality at Dosages Higher than Recommended: Avoid exceeding the recommended dosage of 10 g/m 2daily for three consecutive days. 5.6) Embryo-fetal toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to fetus and to use effective contraception. 5.7, 8.1, 8.3) 5.1 Myelosuppression. Profound myelosuppression with pancytopenia is the desired therapeutic effect of GRAFAPEX-based preparative regimens, occurring in all patients. Time to neutrophil counts 0.5 Gi/L occurred at median of 18 days (range 7-42 days) after allogeneic hematopoietic stem cell transplantation in adult patients treated using GRAFAPEX in combination with fludarabine as the preparative regimen.Do not begin the preparative regimen if the stem cell donor is not available. Monitor blood cell counts daily until hematopoetic recovery. Provide standard supportive care for infections, anemia and thrombocytopenia until there is adequate hematopoietic recovery.. 5.2 Seizures. There have been reports of seizures in patients following treatment with treosulfan. Monitor patients for signs of neurological adverse reactions. Clonazepam prophylaxis may be considered for patients at higher risk for seizures, including infants.. 5.3 Skin Disorders. An increase of skin disorders (e.g. rash, dermatitis) was observed when patients received sodium bicarbonate-containing hydration in the course of treosulfan infusion, potentially because of acceleration of the pH-dependent formation of alkylating epoxides [see Adverse Reactions 6.1) and Clinical Pharmacology 12.1)]. Keep skin clean and dry on days of GRAFAPEX infusion. Diaper dermatitis may occur because of excretion of treosulfan in the urine. Change diapers frequently during the 12 hours after each infusion of GRAFAPEX. Dermatitis may occur under occlusive dressings; change occlusive dressings after each infusion of GRAFAPEX. 5.4 Injection Site Reactions and Tissue Necrosis. GRAFAPEX may cause local tissue necrosis and injection site reactions, including erythema, pain, and swelling, in case of extravasation. Assure venous access patency prior to starting GRAFAPEX infusion, and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of GRAFAPEX. If extravasation occurs, stop the infusion immediately and manage medically as required. Do not administer by the intramuscular or subcutaneous routes.. 5.5 Secondary Malignancies. There is an increased risk of secondary malignancy with use of GRAFAPEX. Treosulfan is carcinogenic and genotoxic [see Nonclinical Toxicology 13.1)] The risk of secondary malignancy is increased in patients with Fanconi anemia and other DNA breakage disorders. The safety and efficacy of GRAFAPEX have not been established for patients with these disorders.. 5.6 Increased Early Morbidity and Mortality at Dosages Higher than Recommended. In MC-FludT.14/L Trial (NCT00822393), 330 adult patients were randomized to treosulfan at 14 g/m 2/day (1.4 times the recommended dose) for three consecutive days or busulfan at 3.2 mg/kg/day for two days, in combination with fludarabine as preparative regimen for allogeneic transplantation. This trial was discontinued early due to higher incidence of early fatal and/or serious adverse reactions in patients receiving treosulfan. Avoid exceeding the recommended GRAFAPEX dosage of 10 g/m 2daily for three consecutive days. 5.7 Embryo-Fetal Toxicity. Based on its mechanism of action, GRAFAPEX can cause fetal harm when administered to pregnant woman because it is genotoxic and affects dividing cells [see Clinical Pharmacology 12) and Nonclinical Toxicology 13)]. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with GRAFAPEX and for months following the last dose of GRAFAPEX. Advise males with female partners of reproductive potential to use effective contraception during treatment with GRAFAPEX and for months after the last dose [see Use in Specific Populations 8.1) and 8.3)].