ALKERAN should be administered in carefully adjusted dosage by or under the supervision of experienced physicians who are familiar with the drug's actions and the possible complications of its use.
As with other nitrogen mustard drugs, excessive dosage will produce marked bone marrow suppression. Bone marrow suppression is the most significant toxicity associated with ALKERAN in most patients. Therefore, the following tests should be performed at the start of therapy and prior to each subsequent course of ALKERAN: platelet count, hemoglobin, white blood cell count, and differential. Thrombocytopenia and/or leukopenia are indications to withhold further therapy until the blood counts have sufficiently recovered. Frequent blood counts are essential to determine optimal dosage and to avoid toxicity (see PRECAUTIONS: Laboratory Tests). Dose adjustment on the basis of blood counts at the nadir and day of treatment should be considered.
Hypersensitivity reactions, including anaphylaxis, have occurred rarely (see ADVERSE REACTIONS). These reactions have occurred after multiple courses of treatment and have recurred in patients who experienced a hypersensitivity reaction to IV ALKERAN. If a hypersensitivity reaction occurs, oral or IV ALKERAN should not be readministered.
Secondary malignancies, including acute nonlymphocytic leukemia, myeloproliferative syndrome, and carcinoma have been reported in patients with cancer treated with alkylating agents (including melphalan). Some patients also received other chemotherapeutic agents or radiation therapy. Precise quantitation of the risk of acute leukemia, myeloproliferative syndrome, or carcinoma is not possible. Published reports of leukemia in patients who have received melphalan (and other alkylating agents) suggest that the risk of leukemogenesis increases with chronicity of treatment and with cumulative dose. In one study, the 10-year cumulative risk of developing acute leukemia or myeloproliferative syndrome after melphalan therapy was 19.5% for cumulative doses ranging from 730 mg to 9,652 mg. In this same study, as well as in an additional study, the 10-year cumulative risk of developing acute leukemia or myeloproliferative syndrome after melphalan therapy was less than 2% for cumulative doses under 600 mg. This does not mean that there is a cumulative dose below which there is no risk of the induction of secondary malignancy. The potential benefits from melphalan therapy must be weighed on an individual basis against the possible risk of the induction of a second malignancy.
Adequate and well-controlled carcinogenicity studies have not been conducted in animals. However, i.p. administration of melphalan in rats (5.4 to 10.8 mg/m2) and in mice (2.25 to 4.5 mg/m2) 3 times per week for 6 months followed by 12 months post-dose observation produced peritoneal sarcoma and lung tumors, respectively.
ALKERAN has been shown to cause chromatid or chromosome damage in humans. Intramuscular administration of ALKERAN at 6 and 60 mg/m2 produced structural aberrations of the chromatid and chromosomes in bone marrow cells of Wistar rats.
Impairment of Fertility
ALKERAN causes suppression of ovarian function in premenopausal women, resulting in amenorrhea in a significant number of patients. Reversible and irreversible testicular suppression have also been reported.
Pregnancy Category D . ALKERAN may cause fetal harm when administered to a pregnant woman. Melphalan was embryolethal and teratogenic in rats following oral (6 to 18 mg/m2/day for 10 days) and intraperitoneal (18 mg/m2) administration. Malformations resulting from melphalan included alterations of the brain (underdevelopment, deformation, meningocele, and encephalocele) and eye (anophthalmia and microphthalmos), reduction of the mandible and tail, as well as hepatocele (exomphaly).
There are no adequate and well-controlled studies in pregnant women. If this drug 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 avoid becoming pregnant.
In all instances where the use of ALKERAN is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse events. ALKERAN should be used with extreme caution in patients whose bone marrow reserve may have been compromised by prior irradiation or chemotherapy, or whose marrow function is recovering from previous cytotoxic therapy. If the leukocyte count falls below 3,000 cells/mcL, or the platelet count below 100,000 cells/mcL, ALKERAN should be discontinued until the peripheral blood cell counts have recovered.
A recommendation as to whether or not dosage reduction should be made routinely in patients with renal insufficiency cannot be made because:
- There is considerable inherent patient-to-patient variability in the systemic availability of melphalan in patients with normal renal function.
- Only a small amount of the administered dose appears as parent drug in the urine of patients with normal renal function.
Patients with azotemia should be closely observed, however, in order to make dosage reductions, if required, at the earliest possible time.
Administration of live vaccines to immunocompromised patients should be avoided.
Information for Patients
Patients should be informed that the major toxicities of ALKERAN are related to bone marrow suppression, hypersensitivity reactions, gastrointestinal toxicity, and pulmonary toxicity. The major long-term toxicities are related to infertility and secondary malignancies. Patients should never be allowed to take the drug without close medical supervision and should be advised to consult their physician if they experience skin rash, vasculitis, bleeding, fever, persistent cough, nausea, vomiting, amenorrhea, weight loss, or unusual lumps/masses. Women of childbearing potential should be advised to avoid becoming pregnant.
Periodic complete blood counts with differentials should be performed during the course of treatment with ALKERAN. At least one determination should be obtained prior to each treatment course. Patients should be observed closely for consequences of bone marrow suppression, which include severe infections, bleeding, and symptomatic anemia (see WARNINGS).
There are no known drug/drug interactions with oral ALKERAN.
Carcinogenesis, Mutagenesis, Impairment of Fertility
See WARNINGS section.
Pregnancy Category D: See WARNINGS section.
It is not known whether this drug is excreted in human milk. ALKERAN should not be given to nursing mothers.
The safety and effectiveness of ALKERAN in pediatric patients have not been established.
Clinical studies of ALKERAN Tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.