Treosulfan

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

1.1 Acute Myeloid Leukemia GRAFAPEX is indicated in combination with fludarabine as a preparative regimen for allogeneic hematopoietic stem cell transplantation in adult and pediatric patients 1 year of age and older with acute myeloid leukemia (AML).

1.2 Myelodysplastic Syndrome GRAFAPEX is indicated in combination with fludarabine as a preparative regimen for allogeneic hematopoietic stem cell transplantation in adult and pediatric patients 1 year of age and older with myelodysplastic syndrome (MDS).

For injection: 1 g/vial or 5 g/vial treosulfan as a white, sterile, lyophilized powder in single-dose vials for reconstitution. For injection: 1 g/vial and 5 g/vial treosulfan as a lyophilized powder in a single-dose vial. ( 3 )

GRAFAPEX is contraindicated in patients with hypersensitivity to any component of the drug product. Hypersensitivity to any component of the drug product. ( 4 )

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 a 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 2 daily for three consecutive days. ( 5.6 ) Embryo-fetal toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a 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 a 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 a 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 I (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 a preparative regimen for allogeneic transplantation. This trial was discontinued early due to a higher incidence of early fatal and/or serious adverse reactions in patients receiving treosulfan. Avoid exceeding the recommended GRAFAPEX dosage of 10 g/m 2 daily for three consecutive days.

5.7 Embryo-Fetal Toxicity Based on its mechanism of action, GRAFAPEX can cause fetal harm when administered to a 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 6 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 3 months after the last dose [see Use in Specific Populations ( 8.1 ) and ( 8.3 )].

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 )] The most common adverse reactions (≥20%) are musculoskeletal pain, stomatitis, pyrexia, nausea, edema, infection, and vomiting. ( 6.1 ) Selected Grade 3 or 4 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 or www.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 a 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 II The safety of GRAFAPEX was evaluated in 553 adult patients with AML and MDS in a randomized trial (MC‑FludT.14/L Trial II) comparing GRAFAPEX in combination with fludarabine to busulfan in combination with fludarabine as a 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 6 hours on day -4 and -3 in combination with fludarabine 30 mg/m 2 daily on day -6, -5, -4, -3 and -2, and hematopoietic stem cell transplantation on day 0 [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 3 or 4 nonhematological laboratory abnormalities were increased GGT, increased bilirubin, increased ALT, increased AST, and increased creatinine. Table 3 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 Reaction* All Grades Grades 3 or 4 GRAFAPEX (N = 270) Busulfan (N = 283) GRAFAPEX (N = 270) Busulfan (N = 283) % % % % Musculoskeletal pain 39 27 5 2 Stomatitis 38 48 6 7 Pyrexia 34 36 1 3 Nausea 33 41 3 6 Edema 29 18 0.7 1 Infection 1 23 18 12 6 Vomiting 22 19 1 1 Rash 17 13 1 1 Diarrhea 17 18 1 1 Headache 16 18 1 1 Febrile neutropenia 15 11 15 11 Abdominal pain 15 13 3 2 Hypertension 14 21 8 10 Hemorrhage 14 14 1 1 Fatigue 13 15 1

0.4 Constipation 12 12 0.4 0 Tachycardia 10 5 1 2 Hepatotoxicity 10 8 4 3 *Includes grouped terms 1 Includes 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 protein All patients treated with GRAFAPEX and fludarabine developed neutropenia, anemia, and thrombocytopenia. One patient on the GRAFAPEX arm had graft failure. Table 4 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 II Laboratory Abnormality GRAFAPEX N = 270 % Busulfan N = 283 % Gamma Glutamyl Transferase Increased 16 28 Bilirubin Increased 6 5 Alanine Aminotransferase Increased 6 4 Aspartate Aminotransferase Increased 4 1 Creatinine Increased 3

0.7 Grading 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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a 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

Certain CYP2C19 and CYP3A4 Substrates: Monitor for adverse reactions of these substrates where minimal concentration changes may lead to serious or life-threatening toxicities. ( 7.1 )

7.1 Effect of GRAFAPEX on Other Drugs Certain CYP2C19 and CYP3A4 Substrates Monitor for adverse reactions of certain CYP2C19 or CYP3A4 substrates where minimal concentration changes may lead to serious or life-threatening toxicities, and reduce the dosage, as needed, if recommended in the prescribing information of these substrates. Treosulfan is a CYP2C19 and CYP3A4 inhibitor [see Clinical Pharmacology ( 12 )] . Concomitant use of GRAFAPEX is predicted to increase the exposure of CYP2C19 and CYP3A4 substrates based on a mechanistic understanding of treosulfan metabolism, which may increase the risk of their adverse reactions.

Lactation: Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on its mechanism of action, GRAFAPEX can cause fetal harm when administered to a 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 a drug-associated risk. Specific embryo-fetal developmental toxicity studies with treosulfan in animals were not conducted. Advise pregnant women of the potential risk to a 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. Data Animal Data Animal 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 Summary There 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 1 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 a pregnant woman [see Use in Specific Populations ( 8.1 )]. Pregnancy Testing Conduct pregnancy testing in females of reproductive potential within 7 days prior to initiating therapy with GRAFAPEX. Contraception Females Advise females of reproductive potential to use effective contraception during and up to 6 months after treatment with GRAFAPEX. Males Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with GRAFAPEX and for 3 months after the last dose [see Nonclinical Toxicology ( 13.1 )] Infertility Based 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 a preparative regimen prior to allogeneic hematopoietic stem cell transplant in pediatric patients 1 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 a preparative regimen prior to allogeneic hematopoietic stem cell transplant in pediatric patients with AML or MDS younger than 1 year of age have not been established. Juvenile Animal Toxicity Data Treatment 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. A 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 a 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.