Melphalan hydrochloride Kit — NDC 71288-132-90 (Billing 71288-0132-90)

WARNINGS Melphalan may cause local tissue damage should extravasation occur, and consequently it should not be administered by direct injection into a peripheral vein. It is recommended that melphalan be administered by injecting slowly into a fast-running intravenous infusion via an injection port, or via a central venous line (see DOSAGE AND ADMINISTRATION: Administration Precautions ). Melphalan 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 melphalan in most patients. Therefore, the following tests should be performed at the start of therapy and prior to each subsequent dose of melphalan: 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. Dose adjustment on the basis of blood counts at the nadir and day of treatment should be considered.

Hypersensitivity reactions including anaphylaxis have occurred in approximately 2% of patients who received the intravenous formulation (see ADVERSE REACTIONS ). These reactions usually occur after multiple courses of treatment. Treatment is symptomatic.

The infusion should be terminated immediately, followed by the administration of volume expanders, pressor agents, corticosteroids, or antihistamines at the discretion of the physician. If a hypersensitivity reaction occurs, intravenous or oral melphalan should not be readministered since hypersensitivity reactions have also been reported with oral melphalan. Carcinogenesis 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 oral melphalan therapy was 19.5% for cumulative doses ranging from 730 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 oral 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, intraperitoneal (IP) administration of melphalan in rats (5.4 to 10.8 mg/m 2 ) and in mice (2.25 to 4.5 mg/m 2 ) 3 times per week for 6 months followed by 12 months post-dose observation produced peritoneal sarcoma and lung tumors, respectively.

Mutagenesis Melphalan has been shown to cause chromatid or chromosome damage in humans. Intramuscular administration of melphalan at 6 and 60 mg/m 2 produced structural aberrations of the chromatid and chromosomes in bone marrow cells of Wistar rats. Impairment of Fertility Melphalan causes suppression of ovarian function in premenopausal women, resulting in amenorrhea in a significant number of patients.

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ADVERSE REACTIONS (SEE OVERDOSAGE ) The following information on adverse reactions is based on data from both oral and intravenous administration of melphalan as a single agent, using several different dose schedules for treatment of a wide variety of malignancies. Hematologic The most common side effect is bone marrow suppression leading to leukopenia, thrombocytopenia, and anemia. White blood cell count and platelet count nadirs usually occur 2 to 3 weeks after treatment, with recovery in 4 to 5 weeks after treatment.

Irreversible bone marrow failure has been reported. Gastrointestinal Gastrointestinal disturbances such as nausea and vomiting, diarrhea, and oral ulceration occur infrequently. Hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice have been reported.

Hepatic veno-occlusive disease has been reported. Hypersensitivity Acute hypersensitivity reactions including anaphylaxis were reported in 2.4% of 425 patients receiving melphalan for myeloma (see WARNINGS ). These reactions were characterized by urticaria, pruritus, edema, skin rashes, and in some patients, tachycardia, bronchospasm, dyspnea, and hypotension.

These patients appeared to respond to antihistamine and corticosteroid therapy. If a hypersensitivity reaction occurs, intravenous or oral melphalan should not be readministered since hypersensitivity reactions have also been reported with oral melphalan. Cardiac arrest has also been reported rarely in association with such reports.

Miscellaneous Other reported adverse reactions include skin hypersensitivity, skin ulceration at injection site, skin necrosis rarely requiring skin grafting, maculopapular rashes, vasculitis, alopecia, hemolytic anemia, allergic reaction, pulmonary fibrosis (including fatal outcomes), and interstitial pneumonitis. Temporary significant elevation of the blood urea has been seen in the early stages of therapy in patients with renal damage. Subjective and transient sensation of warmth and/or tingling.

To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals Inc. at 1-844-824-8426 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Drug Interactions The development of severe renal failure has been reported in patients treated with a single dose of intravenous melphalan followed by standard oral doses of cyclosporine. Cisplatin may affect melphalan kinetics by inducing renal dysfunction and subsequently altering melphalan clearance. Intravenous melphalan may also reduce the threshold for BCNU lung toxicity.

When nalidixic acid and intravenous melphalan are given simultaneously, the incidence of severe hemorrhagic necrotic enterocolitis has been reported to increase in pediatric patients.

PRECAUTIONS General In all instances where the use of melphalan is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse events. Melphalan 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. Dose reduction should be considered in patients with renal insufficiency receiving intravenous melphalan.

In one trial, increased bone marrow suppression was observed in patients with BUN levels ≥30 mg/dL. A 50% reduction in the intravenous melphalan dose decreased the incidence of severe bone marrow suppression in the latter portion of this study. Administration of live vaccines to immunocompromised patients should be avoided.

Information for Patients Patients should be informed that the major acute toxicities of melphalan 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 physicians if they experience skin rash, signs or symptoms of 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. Laboratory Tests Periodic complete blood counts with differentials should be performed during the course of treatment with melphalan. At least 1 determination should be obtained prior to each dose.

Patients should be observed closely for consequences of bone marrow suppression, which include severe infections, bleeding, and symptomatic anemia (see WARNINGS ). Drug Interactions The development of severe renal failure has been reported in patients treated with a single dose of intravenous melphalan followed by standard oral doses of cyclosporine. Cisplatin may affect melphalan kinetics by inducing renal dysfunction and subsequently altering melphalan clearance.

Intravenous melphalan may also reduce the threshold for BCNU lung toxicity. When nalidixic acid and intravenous melphalan are given simultaneously, the incidence of severe hemorrhagic necrotic enterocolitis has been reported to increase in pediatric patients. Carcinogenesis, Mutagenesis, Impairment of Fertility See WARNINGS section.

Pregnancy Teratogenic Effects See WARNINGS section. Nursing Mothers It is not known whether this drug is excreted in human milk. Intravenous melphalan should not be given to nursing mothers.

Pediatric Use The safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of melphalan 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.