Treosulfan

Brand Names: Grafapex

Drug Class: General Prescription

Overview

11 DESCRIPTION GRAFAPEX for injection contains treosulfan, an alkylating drug. Treosulfan is known chemically as L-‑threitol ‑1,4-‑dimethanesulfonate. Treosulfan is soluble in water (7% m/v) at 25ᴼC. Treosulfan is not hygroscopic.Treosulfan has the molecular formula C 6 H 14 O 8 S 2 and a molecular weight of 278.3 g/mole.

Mechanism of Action

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 a prodrug. Treosulfan mean ± SD area under the curve (AUC) is 1,200 ± 211 hr mcg/mL. There was no dose accumulation.

Indications

  • 1 INDICATIONS AND USAGE 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.

Common Doses

  • 10 g
  • 30 mg
  • 0.05 g
  • 1 g

Dosage

2 DOSAGE AND ADMINISTRATION Recommended dosage: 10 g/m² body surface area (BSA) per day as a 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 ) 2.1 Recommended Dosage The recommended dosage of GRAFAPEX is 10 g/m 2 by intravenous infusion given daily for three days, beginning on Day -4 prior to transplantation in combination with fludarabine as outlined in Table 1.

Black Box Warning

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 )] . WARNING: MYELOSUPPRESSION See 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.

Contraindications

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

Side Effects

  • 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 )] The most common adverse reactions (≥20%) are musculoskeletal pain, stomatitis, pyrexia, nausea, edema, infection, and vomiting. ( 6.

Interactions

  • 7 DRUG INTERACTIONS 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.