INDICATIONS AND USAGE Melphalan Hydrochloride for Injection is indicated for the palliative treatment of patients with multiple myeloma for whom oral therapy is not appropriate.

WARNINGS Melphalan Hydrochloride for Injection 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 Hydrochloride for Injection be administered by injecting slowly into a fast-running IV 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 Hydrochloride for Injection in most patients.

Therefore, the following tests should be performed at the start of therapy and prior to each subsequent dose of Melphalan Hydrochloride for Injection: 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 IV 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, IV 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.

Reversible and irreversible testicular suppression have also been reported.

Pregnancy Pregnancy Category D Melphalan may cause fetal harm when administered to a pregnant woman.

While adequate animal studies have not been conducted with IV melphalan, oral (6 to 18 mg/m 2 /day for 10 days) and IP (18 mg/m 2 ) administration in rats was embryolethal and teratogenic.

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.

ADVERSE REACTIONS (SEE OVERDOSAGE) The following information on adverse reactions is based on data from both oral and IV 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 Hydrochloride for Injection 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, IV 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 Avenacy Inc.

at 1-855-283-6229 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .