Grafapex Drug Information

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).

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).

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 . 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

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

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

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 . 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.

is contraindicated in patients with hypersensitivity to any component of the drug product. Hypersensitivity to any component of the drug product.

The principal toxic effect of treosulfan in cases of overdose are myeloablation and prolonged pancytopenia, mucositis, skin toxicity, nausea, vomiting and gastritis. In case of overdosage, monitor blood counts frequently and provide vigorous supportive measures as medically indicated.