Warnings and Precautions
Myelosuppression: Profound myelosuppression with pancytopenia is the desired therapeutic effect of a GRAFAPEX-based preparative regimen, occurring in all patients. Do not begin the preparative regimen if the stem cell donor is not available. Monitor blood cell counts at least daily until hematopoietic recovery. Provide standard supportive care for infections, anemia, and thrombocytopenia until there is adequate hematopoietic recovery.
Seizures: Monitor patients for signs of neurological adverse reactions, including seizure. Clonazepam prophylaxis may be considered for patients at higher risk for seizures, including infants.
Skin Disorders: An increase in skin disorders (eg, rash, dermatitis) was observed when patients received sodium bicarbonate–containing hydration in the course of treosulfan infusion. 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.
Injection Site Reactions and Tissue Necrosis: Treosulfan may cause local tissue necrosis and injection site reactions, including erythema, pain, and swelling, in cases 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 intramuscular or subcutaneous routes.
Secondary Malignancies: There is an increased risk of a secondary malignancy with the use of GRAFAPEX. Treosulfan is carcinogenic and genotoxic.
The risk of secondary malignancy is increased in patients with Fanconi anemia and other DNA breakage disorders. The safety of GRAFAPEX has not been established for patients with these disorders.
Increased Early Morbidity and Mortality at Dosages Higher Than Recommended: A higher incidence of early fatal and/or serious adverse reactions has been observed in patients receiving treosulfan at dosages of 14 g/m2 (1.4 times the recommended dose). Avoid exceeding the recommended GRAFAPEX dosage of 10 g/m2 daily for three consecutive days.
Embryo-Fetal Toxicity: GRAFAPEX can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception.
Adverse Reactions
The most common adverse reactions (≥20%) in patients treated with GRAFAPEX were musculoskeletal pain, stomatitis, pyrexia, nausea, edema, infection, and vomiting. Select Grade 3 or 4 nonhematological laboratory abnormalities were increased GGT, increased bilirubin, increased ALT, increased AST, and increased creatinine.
Drug Interactions
Effect of GRAFAPEX on Other Drugs (Certain CYP2C19 and CYP3A Substrates): 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 adverse reactions.
Use in Specific Populations
- Pregnancy: GRAFAPEX can cause fetal harm. 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.
- Lactation: There is no data on the presence of treosulfan or its metabolites in human milk, its effects on milk production, or the effects of treosulfan on the breastfed child. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with GRAFAPEX and for at least 1 week after the last dose.
- Patients With Renal Impairment: No dosage adjustment is recommended for patients with mild renal impairment (creatinine clearance [CLcr] 60–89 mL/min). The effect of moderate or severe renal impairment and age >65 years on GRAFAPEX pharmacokinetics is unknown.
- Pediatric Use: The safety profile in children 1 year of age and older is comparable to that seen in adult patients, except that the incidence of hepatic and gastrointestinal toxicities was higher in pediatric patients than in adults.
- Geriatric Use: No significant differences in safety or effectiveness were observed between elderly subjects and younger subjects.
- Hepatic Impairment: No dosage adjustment is recommended for patients with mild hepatic impairment (total bilirubin less than or equal to upper limit of normal [ULN] with aspartate aminotransferase [AST] greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST). The effect of moderate or severe hepatic impairment and age >65 years on GRAFAPEX pharmacokinetics is unknown.
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