GRAFAPEX treosulfan 5000 mg/5g Injection, Powder, Lyophilized, For Solution
🆔 Identity & classification
Where does this data come from?
🏷️ RxNorm drug class
This medicine belongs to the Alkyl sulfonates class.
Where does this data come from?
🏭 Manufacturer & labeler
Where does this data come from?
🩺 Clinical
Patient education
Supplement & herbal interactions
Where does this data come from?
Ask a licensed pharmacist directly — free, answered by our team.
🧪 Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
Where does this data come from?
IACT rows and label-wide narrative are kept separate; availability and product-level specificity depend on the submitted label.Inactive ingredient FAQ
Are inactive ingredients the same for every manufacturer?
Why might an inactive ingredient be missing?
Can inactive ingredients matter?
💲 Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per mL | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | Not in the retail survey — common for institutional, discontinued, or low-volume packs. | |
| Medicaid paysCMS SDUD · 12 mo | No recent Medicaid claims on file for this NDC — rare and low-volume NDCs are suppressed in the public data. | |
| Medicare drug plans payPart D · quarterly | No Part D plan price is available for this NDC in our data. | |
| Medicare Part B allowsASP · J0614 | $32.330 / J0614 unit | — |
Where does this data come from?
🧾 Billing & reimbursement
Where does this data come from?
🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Grafapex 5000 mg/5gthis 59137-0365-01 | Medexus | 1 vial | — | — | FDA listed | — |
Where does this data come from?
⏳ Availability & generic status
We did not find an FDA-approved generic match for this exact strength, form and route. Patent/protection dates below may affect future generic timing.
Why the date isn’t exact: Generic timing can change because patents may be challenged, settled, licensed, added, removed, or worked around with a narrower label — and FDA approval does not always mean a pharmacy can get the generic today.
🛈 What do these terms mean?
- Patent
- Legal protection listed in the Orange Book that may delay generic approval or launch. Issued by the U.S. Patent & Trademark Office.
- Substance patent
- Covers the active drug molecule itself — the hardest to design around. A generic generally can’t launch until it expires.
- Formulation (product) patent
- Covers a specific formulation or dosage form. A generic can sometimes work around it with a different formulation.
- Method-of-use patent
- A patent covering one specific approved use of the drug — not necessarily the whole molecule. A generic can sometimes launch with a “skinny label” that carves out the protected use and keeps the others.
- Skinny label
- A generic label that omits a still-patented use when the FDA allows it — letting a generic reach the market for the unprotected uses.
- Exclusivity
- FDA-granted marketing protection, separate from patents — e.g. 5-yr new chemical entity, 7-yr orphan drug, or a +6-month pediatric extension.
- Paragraph IV
- A generic applicant’s formal challenge to a listed patent. It can potentially lead to earlier generic entry, but often involves litigation or a settlement.
- RLD / RS
- Reference Listed Drug — the brand product the FDA uses as the reference for generic applications. Reference Standard — the product the FDA expects generics to compare against in bioequivalence testing.
- TE / AB rating
- FDA therapeutic-equivalence rating. An AB rating generally means the FDA considers a generic therapeutically equivalent to — and substitutable for — the brand.
- LOE (loss of exclusivity)
- The latest patent or exclusivity currently listed — the loss-of-exclusivity / latest-listed-protection date shown on this page. Paragraph-IV challenges and settlements can move the real date earlier; FDA approval and a manufacturer’s decision to market can move it later.
Built from the FDA Orange Book. The bars above are scaled to each protection’s expiry; the red LOE marker is the last one to lapse.
| Patent | Type | Use code | Expires |
|---|---|---|---|
| US 7199162 ↗ | Method of use | U-4142 | Oct 12, 2026 |
| US 7199162 ↗ | Method of use | U-4142 | Oct 12, 2026 |
| Code | What it grants | Expires |
|---|---|---|
| NCE | New Chemical Entity (5-year) | Jan 21, 2030 |
| ODE-513 | Orphan Drug Exclusivity (7-year) | Jan 21, 2032 |
| ODE-514 | Orphan Drug Exclusivity (7-year) | Jan 21, 2032 |
| NCE | New Chemical Entity (5-year) | Jan 21, 2030 |
| ODE-513 | Orphan Drug Exclusivity (7-year) | Jan 21, 2032 |
| ODE-514 | Orphan Drug Exclusivity (7-year) | Jan 21, 2032 |
Is there a generic version of GRAFAPEX 5 GRAM VIAL?
The FDA approved a generic — why can’t I get it at my pharmacy yet?
Why do different websites show different generic release dates?
What does “FDA listed” mean?
What does a patent or protection date mean here?
What does “current Orange Book estimate” mean?
Can a generic come out before the last patent expires?
Can a generic come out after the listed dates?
What is the difference between patents and exclusivity?
Why are there multiple patent dates?
Where does this data come from?
🔬 Reported adverse events (FAERS)
Top reported reactions
Age at onset
Reporter sex
Serious outcomes
Where does this data come from?
📦 Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Status |
|---|---|---|---|
| 59137-0365-01 You're viewing this | 1 VIAL in 1 CARTON (59137-365-01) / 5 g in 1 VIAL | 2025-01-28 | Active |
🧭 About this NDC listing & data coverage
What data is (and isn’t) available for this NDC — tap to expand
| NDC identity (package / product / labeler codes) | ✓ Available |
| Labeler | ✓ Available |
| Product & package description | ✓ Available |
| Marketing category & status | ✓ Available |
| Active ingredient / dosage form / route | ✓ Available |
| FDA label (SPL via DailyMed) | ✓ Available |
| Package photos | ✓ Available |
| Inactive ingredients (structured) | — Not published for this NDC The labeler did not submit a structured excipient list, or no SPL is available. |
| NADAC pharmacy acquisition price (CMS) | — Not published for this NDC CMS publishes NADAC only for NDCs reported in its retail-pharmacy survey. |
| Orange Book / therapeutic-equivalence data | ✓ Available |
| HCPCS J-code billing crosswalk | ✓ Available |
| Medicaid utilization (CMS SDUD) | — Not published for this NDC CMS reports utilization only for NDCs with Medicaid claims above its privacy threshold. |
Questions about this listing
Why is there no price listed?
Is the NDC printed on the package the same as the 11-digit billing NDC?
What do the three segments of this NDC mean?
Is this package still being marketed?
Who lists this product with the FDA?
Do I need a prescription for this product?
Does this product have a billing J-code?
Where does this data come from?
📄 Full prescribing information FDA SPL
🚨 Boxed 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.
Monitor hematologic laboratory parameters. ( 5.1 )
🎯 Indications and Usage ▾
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 ).
1.1Acute 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).
1.2Myelodysplastic 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).
⏱️ Dosage and Administration ▾
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 )
2.1Recommended 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. Table 1: Dosage Regimen for GRAFAPEX-Based Allogeneic HSCT Treatment Day -6 Day -5 Day -4 Day-3 Day -2 Day -1 Day 0 GRAFAPEX 10 g/m 2 /day intravenous infusion X X X Fludarabine 30 mg/m 2 /day intravenous infusion X X X X X Allogeneic hematopoietic stem cell infusion X Premedicate patients with antiemetics prior to the first dose of GRAFAPEX and continue antiemetics on a fixed schedule through completion of treosulfan administration.
2.2Preparation and Administration Instructions Reconstitute GRAFAPEX prior to intravenous infusion. GRAFAPEX is a hazardous drug. Follow applicable special handling and disposal procedures.
1 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 2 to obtain a 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 Volume Strength Volume 1 g/vial 20 mL 5 g/vial 100 mL Shake the vial(s) to dissolve. Inspect the reconstituted solution for discoloration and particulate matter.
The reconstituted solution appears as a 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 a 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 20°C to 25°C (68°F to 77°F) for up to 24 hours. Do not use if the solution contains a precipitate. Do not refrigerate.
Infuse GRAFAPEX intravenously over 2 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 )] .
💊 Dosage Forms and Strengths ▾
3 DOSAGE 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. For injection: 1 g/vial and 5 g/vial treosulfan as a lyophilized powder in a single-dose vial. ( 3 )
⛔ 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 )
⚠️ Warnings and Cautions ▾
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 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 )
5.1Myelosuppression Profound myelosuppression with pancytopenia is the desired therapeutic effect of GRAFAPEX-based preparative regimens, occurring in all patients. Time to neutrophil counts >
0.5Gi/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.
5.2Seizures 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.
5.3Skin 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.
5.4Injection 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.
5.5Secondary 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.
5.6Increased 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…
🤒 Adverse Reactions ▾
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.
( 6.1 ) 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 .
6.1Clinical 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 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
0.4Constipation 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
4.03Clinically 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 an…
🔄 Drug 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 )
7.1Effect 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.
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 )
8.1Pregnancy 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.
8.2Lactation 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.
8.3Females 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 )] .
8.4Pediatric 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%…
🆘 Overdosage ▾
10 OVERDOSAGE 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.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism 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.
12.2Pharmacodynamics Increase in treosulfan exposure was associated with an increased incidence of infection-related death. Treosulfan time course of pharmacodynamic response is unknown.
12.3Pharmacokinetics 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. Distribution Treosulfan mean (CV%) volume of distribution is approximately 41 liters (CV%: 19%). Treosulfan does not bind to plasma albumin.
Elimination Treosulfan mean (± standard deviation) terminal half-life is 1.7 ± 0.4 hours. Metabolism The 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). Excretion A 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 8 hours after administration.
Specific Populations No 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 1 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 Patients Treosulfan exposure in pediatric patients with BSA < 0.7 m 2 and with BSA 0.7 to < 1.1 m 2 are 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 Studies In Vitro Studies CYP Enzymes : Treosulfan is a CYP2D6 substrate and its monoepoxide intermediate is a 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.
📦 How Supplied / Storage and Handling ▾
16 HOW 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. Presentation NDC 1 g/vial 59137-335-01 5 g/vial 59137-365-01 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 1 .
📋 Description ▾
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. Treosulfan has the following chemical structure: 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.
Treosulfan Chemical Structure
💬 Information for Patients ▾
17 PATIENT 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 [see Warnings and Precautions ( 5.1 )] . Seizures Inform patients that seizures may occur [ see Warnings and Precautions ( 5.2 )] .
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” [see Warnings and Precautions ( 5.3 )] . Secondary Malignancies Inform patients of the possible risk of a second malignancy [see Warnings and Precautions ( 5.5 )] .
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 [see Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use effective contraception during treatment with GRAFAPEX and for 6 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 3 months after the last dose [see Warnings and Precautions ( 5.7 ) and Use in Specific Populations ( 8.3 )] .
Lactation Advise women not to breastfeed during treatment with GRAFAPEX and for 1 week after the last dose [see Use in Specific Populations ( 8.2 )]. Infertility GRAFAPEX 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™ is a trademark of medac GmbH, Germany.