Special Warning : אזהרת שימוש

7.   WARNINGS

BUSULFAN RAZ 6 MG/ML, is a potent cytotoxic drug that results in profound myelosuppression at the recommended dosage. It should be administered under the supervision of a qualified physician who is experienced in the use of cancer chemotherapeutic agents and in the management of patients with severe pancytopenia. Appropriate management of therapy and complications is only possible when adequate diagnostic and treatment facilities are readily available.

The most frequent, serious consequence of treatment with BUSULFAN RAZ 6 MG/ML at the recommended dose and schedule is profound myelosuppression, occurring in all patients. Severe granulocytopenia, thrombocytopenia, anemia, or any combination thereof may develop. Frequent complete blood counts, including white blood cell differentials, and quantitative platelet counts should be monitored during treatment and until recovery is achieved. Absolute neutrophil counts <0.5x109/L at a median of 4 days post-transplant occurred in 100% of patients and recovered at median day 10 following transplant (median neutropenic period of 6 days). Prophylactic or empiric use of anti-infectives (bacterial, fungal, viral) should be considered for prevention and management of infections during the neutropenic period. Thrombocytopenia (<25,000/mm3 or requiring platelet transfusion) at a median of 5-6 days occurred in 98% of patients. Anemia (hemoglobin <8.0 g/dL) occurred in 69% of patients. Platelet and red blood cell support should be employed as medically indicated.

Busulfan may be a human carcinogen. Secondary malignancy has been reported in patients treated with BUSULFAN RAZ 6 MG/ML. Several cases of leukemia have occurred 5-8 years following oral busulfan treatment. Busulfan may also cause cellular dysplasia.
BUSULFAN RAZ 6 MG/ML may cause temporary or permanent infertility in females and males.
Ovarian suppression and amenorrhea commonly occur in premenopausal women undergoing chronic, low-dose busulfan therapy for chronic myelogenous leukemia. Sterility, azoospermia, and testicular atrophy have been reported in male patients.
Bronchopulmonary dysplasia with pulmonary fibrosis is a rare complication following chronic busulfan therapy. The average onset of symptoms is after 4 years of therapy (range 4 months to 10 years).

Pregnancy:
Busulfan can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. BUSULFAN RAZ 6 MG/ML should not be administered to pregnant women or women who may possibly be pregnant. If BUSULFAN RAZ 6 MG/ML is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use effective contraception during and up to 6 months after treatment.
BUSULFAN RAZ 6 MG/ML may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Men treated with BUSULFAN RAZ 6 MG/ML are advised not to father a child during and up to 6 months after treatment.

Nursing Mothers:
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for busulfan in human and animal studies, breast-feeding should be discontinued during treatment with BUSULFAN RAZ 6 MG/ML. The safety of BUSULFAN RAZ 6 MG/ML in nursing women has not been established.

Hepatic Insufficiency:
BUSULFAN RAZ 6 MG/ML has not been administered to patients with hepatic insufficiency.
However, patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or a prior progenitor cell transplant may be at an increased risk of developing hepatic veno-occlusive disease with the recommended BUSULFAN RAZ 6 MG/ML dose and regimen (see ADVERSE REACTIONS).

8.   PRECAUTIONS

General:
At the recommended dosage of BUSULFAN RAZ 6 MG/ML, profound myelosuppression is universal, and can be manifested as neutropenia, thrombocytopenia, anemia, or a combination thereof. The patient should be monitored for signs of local or systemic infection or bleeding and their hematologic status evaluated frequently.

Caution should be exercised when administering the recommended dose of BUSULFAN RAZ 6 MG/ML to patients with a history of seizure disorder, head trauma, or receiving other potentially epileptogenic drugs. It is recommended that appropriate anti-convulsant therapy be administered prophylactically to such patients (see Drug Interactions). Seizures have been reported with high dose oral busulfan treatment.

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