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. Treosulfan is a CYP2C19 and CYP3A4 inhibitor <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12 )]</span> . 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.
GRAFAPEX is contraindicated in patients with hypersensitivity to any component of the drug product. Hypersensitivity to any component of the drug product. ( 4 )
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 )
5.1 Myelosuppression Profound myelosuppression with pancytopenia is the desired therapeutic effect of GRAFAPEX-based preparative regimens, occurring in all patients. Time to neutrophil counts >
0.5 Gi/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.
5.2 Seizures 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.
5.3 Skin 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 ) and Clinical Pharmacology ( 12.1 )]</span>. 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.
5.4 Injection 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.
5.5 Secondary Malignancies There is an increased risk of a secondary malignancy with use of GRAFAPEX. Treosulfan is carcinogenic and genotoxic <span class="opacity-50 text-xs">[see Nonclinical Toxicology ( 13.1 )]</span> . 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.
5.6 Increased 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 trial was discontinued early due to a higher incidence of early fatal and/or serious adverse reactions in patients receiving treosulfan. Avoid exceeding the recommended GRAFAPEX dosage of 10 g/m 2 daily for three consecutive days.
5.7 Embryo-Fetal Toxicity 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12 ) and Nonclinical Toxicology ( 13 )]</span>. Advise pregnant women of the potential risk to the fetus. 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 ) and ( 8.3 )]</span>.