Brand Name
Grafapex
Generic Name
Treosulfan
View Brand Information FDA approval date: January 28, 2025
Form: Injection
What is Grafapex (Treosulfan)?
GRAFAPEX is an alkylating drug indicated for: 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 acute myeloid leukemia .
Approved To Treat
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Brand Information
GRAFAPEX (treosulfan)
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 ( .
1DOSAGE FORMS AND STRENGTHS
For injection: 1 g/vial or 5 g/vial treosulfan as a white, sterile, lyophilized powder in single-dose vials for reconstitution.
2CONTRAINDICATIONS
GRAFAPEX is contraindicated in patients with hypersensitivity to any component of the drug product.
3ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Myelosuppression
- Seizures
- Skin Disorders
- Injection Site Reactions and Tissue Necrosis
- Secondary Malignancies
3.1Clinical 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
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.
Clinically relevant adverse reactions in <10% of patients who received GRAFAPEX included:
Neoplasms benign, malignant and unspecified (including cysts and polyps): second malignancy
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.
3.2Postmarketing 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
4OVERDOSAGE
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.
5DESCRIPTION
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
GRAFAPEX is intended for intravenous administration. It is supplied as a white, sterile, lyophilized powder for injection in glass vials containing 1 g or 5 g treosulfan.
6CLINICAL STUDIES
The efficacy of GRAFAPEX was evaluated in a randomized active-controlled trial (MC‑FludT.14/L Trial II;
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 6 hours on day -4 and -3 in combination with fludarabine 30 mg/m
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 5 shows the baseline characteristics of the study patients.
Efficacy 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 3 below.
Figure 1: Kaplan-Meier estimates of overall survival since time of randomization MC FludT.14/L Trial II
Figure 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)
7REFERENCES
“OSHA Hazardous Drugs.” OSHA.
8HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
GRAFAPEX (treosulfan) for injection is a white, sterile, lyophilized powder for reconstitution. It is supplied in a carton containing one single-dose vial.
Storage and Handling
Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. (Excursions permitted between 15°C and 30°C)
GRAFAPEX is a hazardous drug. Follow applicable special handling and disposal procedures
9PATIENT COUNSELING INFORMATION
Infections
- 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
Seizures
- Inform patients that seizures may occur
Skin Disorders
- Advise patients to clean “sweaty” skin parts (armpit, groin, genital area, inframammary line), each with a 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”
Secondary Malignancies
- Inform patients of the possible risk of a second malignancy
Embryo-Fetal Toxicity
- Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy
- 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
Lactation
- Advise women not to breastfeed during treatment with GRAFAPEX and for 1 week after the last dose
Infertility
- GRAFAPEX can impair fertility in females and males, and may cause temporary or permanent infertility
Manufactured for:
GRAFAPEX™ is a trademark of medac GmbH, Germany.
10PRINCIPAL DISPLAY PANEL - GRAFAPEX™ 1 g
Carton Label - GRAFAPEX™ 1 g
NDC 59137- 335-01
GRAFAPEX™
(treosulfan) for injection
1 g/vial
(treosulfan) for injection
1 g/vial
For intravenous infusion
after reconstitution
after reconstitution
WARNING: Hazardous Drug
One Single-dose Vial.
Rx only
One Single-dose Vial
Vial Label - GRAFAPEX™ 1 g
NDC59137 -335-00
GRAFAPEX™
(treosulfan)
for injection
1 g/vial
(treosulfan)
for injection
1 g/vial
For intravenous infusion
WARNING: Hazardous Drug
Single-dose Vial.
Recommended dosage: See Prescribing
Rx only
Manufactured for: Medexus Pharma, Inc.
Manufactured by:
11PRINCIPAL DISPLAY PANEL - GRAFAPEX™ 5 g
Carton Label - GRAFAPEX™ 5 g
NDC59137- 365-01
GRAFAPEX™
(treosulfan) for injection
5 g/vial
(treosulfan) for injection
5 g/vial
For intravenous infusion
WARNING: Hazardous Drug
One Single-dose Vial.
Rx only
Vial Label - GRAFAPEX™ 5 g
NDC59137- 365-00
GRAFAPEX™
(treosulfan)
for injection
5 g/vial
GRAFAPEX™
(treosulfan)
for injection
5 g/vial
For intravenous infusionafter reconstitution
WARNING: Hazardous Drug
Single-dose Vial.
Recommended dosage: See Prescribing
Rx only
Manufactured for: Medexus Pharma, Inc.
Manufactured by:
