Melphalan

— THERAPEUTIC CATEGORIES —
  • Gynecologic cancers
  • Leukemias, lymphomas, and other hematologic cancers
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Melphalan Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Melphalan 2mg; scored tabs.

    Pharmacological Class

    Alkylating agent.

    See Also

      How Supplied

      Contact supplier

      Manufacturer

      Alvogen

      Melphalan Indications

      Indications

      For the palliation of non-resectable epithelial ovarian cancer.

      Melphalan Dosage and Administration

      Adult

      0.2mg/kg per day for 5 days; repeat course every 4–5 weeks. Continue treatment as hematological recovery permits (esp. WBCs and platelets); for other regimens: see full labeling.

      Children

      Not recommended.

      Melphalan Contraindications

      Contraindications

      Prior resistance to melphalan.

      Melphalan Boxed Warnings

      Boxed Warning

      Should be administered under the supervision of an experienced physician in cancer chemotherapeutic agents. May cause severe bone marrow suppression with resulting infection or bleeding. Leukemogenic in humans. Potentially mutagenic.

      Melphalan Warnings/Precautions

      Warnings/Precautions

      Prior irradiation or chemotherapy. Bone marrow suppression. Azotemia. Monitor platelets, hemoglobin, WBC and differential at start of therapy and prior to each course; discontinue if WBC <3,000cells/µL or platelets <100,000cells/µL. Moderate to severe renal impairment. Elderly. Pregnancy (Cat.D), nursing mothers: not recommended.

      Warnings/Precautions

      • Administer melphalan under the supervision of an experienced physician in cancer chemotherapeutic agents. 

      • Monitor platelets, hemoglobin, WBC and differential at start of therapy and prior to each course. Discontinue melphalan if leukocyte count < 3000 cells/mcL or platelet count < 100,000 cells/mcL until the peripheral blood cell counts have recovered.

      • Withhold further therapy if thrombocytopenia and/or leukopenia occur until the blood counts have sufficiently recovered.

      • Consider adjusting dose on the basis of blood counts at the nadir and day of treatment.

      • Do not readminister oral or IV melphalan if hypersensitivity reactions occur, including anaphylaxis.

      • Secondary malignancies (e.g., acute nonlymphocytic leukemia, myeloproliferative syndrome, carcinoma) have been reported in patients with cancer treated with alkylating agents, including melphalan. The potential benefits and risks from melphalan therapy must be weighed on an individual basis.

      • Use 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.

      • Monitor closely in patients with azotemia.

      • Avoid administration of live vaccines to immunocompromised patients.

      • Laboratory Tests: Obtain periodic CBCs with differentials during treatment. Obtain at least 1 determination prior to each treatment course. Monitor patients closely for consequences of bone marrow suppression, including severe infections, bleeding, and symptomatic anemia.

      Pregnancy Considerations

      Pregnancy Category D

      • May cause fetal harm. Melphalan was embryo-lethal and teratogenic in rats.

      • There are no adequate and well-controlled studies in pregnant women.

      • Women of childbearing potential should avoid becoming pregnant.

      Nursing Mother Considerations

      Not known whether melphalan is excreted in human milk. Do not administer to nursing mothers.

      Pediatric Considerations

      Safety and effectiveness of melphalan tablets in pediatric patients have not been established.

      Geriatric Considerations

      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. 

      Melphalan Pharmacokinetics

      Absorption

      The absorption of oral melphalan is highly variable with respect to both the time to first appearance of the drug in plasma (range: 0 to 6 hours) and peak plasma concentration (C). The average absolute bioavailability of melphalan is also highly variable (range: 56% to 93%). Oral administration of melphalan with a high fat meal may reduce melphalan exposure (AUC) by 36% to 54%.

      Distribution

      The steady-state volume of distribution of melphalan is 0.5 L/kg. The average melphalan binding to plasma proteins is highly variable (range: 53% to 92%).

      Elimination

      Half-life: 1.5 ± 0.83 hours. 

      Melphalan Interactions

      Interactions

      Radiotherapy potentiates antineoplastic effect. For IV: caution with cyclosporine, cisplatin, BCNU, nalidixic acid.

      Melphalan Adverse Reactions

      Adverse Reactions

      Bone marrow suppression, GI upset, hepatic dysfunction, anemia, blood dyscrasias, secondary malignancies (eg, nonlymphocytic leukemia), rash, alopecia, pulmonary fibrosis, interstitial pneumonitis, gonadal toxicity (amenorrhea, infertility); hypersensitivity reactions, cardiac arrest (rare).

      Adverse Reactions

      • Hematologic: Bone marrow suppression leading to leukopenia, thrombocytopenia, and anemia. Irreversible bone marrow failure has been reported.

      • Gastrointestinal: Nausea, vomiting, diarrhea, oral ulceration. Hepatic disorders ranging from abnormal liver function tests to hepatitis and jaundice have been reported. Hepatic veno-occlusive disease has been reported.

      • Miscellaneous: Other reported adverse reactions include pulmonary fibrosis (including fatal outcomes) and interstitial pneumonitis, skin hypersensitivity, maculopapular rashes, vasculitis, alopecia, and hemolytic anemia. Allergic reactions have occurred.

      Melphalan Clinical Trials

      See Literature

      Melphalan Note

      Notes

      Formerly known under the brand name Alkeran.

      Melphalan Patient Counseling

      Patient Counseling

      Advise patients that major toxicities of melphalan tablets are related to bone marrow suppression, hypersensitivity reactions, gastrointestinal toxicity, and pulmonary toxicity.

      Advise patients that the major long-term toxicities are related to infertility and secondary malignancies.

      Do not take melphalan without close medical supervision. Advise patients to consult their health care provider if they experience skin rash, vasculitis, bleeding, fever, persistent cough, nausea, vomiting, amenorrhea, weight loss, or unusual lumps/masses.

      Advise women of childbearing potential to avoid becoming pregnant.

      Melphalan Generic Name & Formulations

      Legal Class

      Rx

      General Description

      Melphalan 2mg; scored tabs.

      Pharmacological Class

      Alkylating agent.

      See Also

      How Supplied

      Contact supplier

      Manufacturer

      Alvogen

      Melphalan Indications

      Indications

      Palliative treatment for multiple myeloma.

      Melphalan Dosage and Administration

      Adult

      6mg once daily for 2–3 weeks; stop for up to 4 weeks, maintenance 2mg per day. Continue treatment as hematological recovery permits (esp. WBCs and platelets); for other regimens: see full labeling.

      Adult

      Usual oral dose: 6 mg (3 tablets) daily for 2 to 3 weeks of treatment; may give the entire daily dose at one time. Adjust dose based on blood counts obtained at approximately weekly intervals.

      After 2 to 3 weeks of treatment, discontinue melphalan for up to 4 weeks - at which the blood count should be followed carefully.

      May institute maintenance dose of 2 mg daily if WBC and platelet counts rise.

      Response may be very gradual over many months. Important to give repeated courses or continuous therapy since improvement may continue slowly over many months.

      Dosage Regimens Used by Various Investigators

      • Due to the patient-to-patient variation in melphalan plasma levels, several investigators have recommended to cautiously escalate the dosage of melphalan until some myelosuppression is observed to assure potentially therapeutic levels have been reached.

      • Osserman and Takatsuki - initial course of 10 mg/day for 7 to 10 days. According to these investigators, maximal suppression of leukocyte and platelet counts occur within 3 to 5 weeks and recovery within 4 to 8 weeks. Institute continuous maintenance therapy with 2 mg/day when WBC >4000 cells/mcL and platelet count >100,000 cells/mcL. Adjust dose between 1 mg/day and 3 mg/day depending on the hematological response.

      • Hoogstraten et al - initial course of 0.15 mg/kg/day for 7 days, followed by a rest period of at least 14 days (it may be as long as 5 to 6 weeks). Initiate maintenance therapy of 0.05 mg/kg/day or less when WBC and platelet counts are rising. Adjust maintenance dose according to the blood count.

      • One study by Alexaninan et al have shown that the use of melphalan in combination with prednisone significantly improves the percentage of patients with multiple myeloma who achieve palliation. 

      • Other investigators have administered courses of melphalan tablets at 0.25 mg/kg/day for 4 consecutive days (or, 0.20 mg/kg/day for 5 consecutive days) for a total dose of 1 mg/kg/course. Repeat the 4- to 5-day courses every 4 to 6 weeks if the granulocyte count and platelet count have returned to normal levels.

      Children

      Not recommended.

      Melphalan Contraindications

      Contraindications

      Prior resistance to melphalan.

      Melphalan Boxed Warnings

      Boxed Warning

      Should be administered under the supervision of an experienced physician in cancer chemotherapeutic agents. May cause severe bone marrow suppression with resulting infection or bleeding. Leukemogenic in humans. Potentially mutagenic.

      Melphalan Warnings/Precautions

      Warnings/Precautions

      Prior irradiation or chemotherapy. Bone marrow suppression. Azotemia. Monitor platelets, hemoglobin, WBC and differential at start of therapy and prior to each course; discontinue if WBC <3,000cells/µL or platelets <100,000cells/µL. Moderate to severe renal impairment. Elderly. Pregnancy (Cat.D), nursing mothers: not recommended.

      Warnings/Precautions

      • Administer melphalan under the supervision of an experienced physician in cancer chemotherapeutic agents. 

      • Monitor platelets, hemoglobin, WBC and differential at start of therapy and prior to each course. Discontinue melphalan if leukocyte count < 3000 cells/mcL or platelet count < 100,000 cells/mcL until the peripheral blood cell counts have recovered.

      • Withhold further therapy if thrombocytopenia and/or leukopenia occur until the blood counts have sufficiently recovered.

      • Consider adjusting dose on the basis of blood counts at the nadir and day of treatment.

      • Do not readminister oral or IV melphalan if hypersensitivity reactions occur, including anaphylaxis.

      • Secondary malignancies (e.g., acute nonlymphocytic leukemia, myeloproliferative syndrome, carcinoma) have been reported in patients with cancer treated with alkylating agents, including melphalan. The potential benefits and risks from melphalan therapy must be weighed on an individual basis.

      • Use 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.

      • Monitor closely in patients with azotemia.

      • Avoid administration of live vaccines to immunocompromised patients.

      • Laboratory Tests: Obtain periodic CBCs with differentials during treatment. Obtain at least 1 determination prior to each treatment course. Monitor patients closely for consequences of bone marrow suppression, including severe infections, bleeding, and symptomatic anemia.

      Pregnancy Considerations

      Pregnancy Category D

      • May cause fetal harm. Melphalan was embryo-lethal and teratogenic in rats.

      • There are no adequate and well-controlled studies in pregnant women.

      • Women of childbearing potential should avoid becoming pregnant.

      Nursing Mother Considerations

      Not known whether melphalan is excreted in human milk. Do not administer to nursing mothers.

      Pediatric Considerations

      Safety and effectiveness of melphalan tablets in pediatric patients have not been established.

      Geriatric Considerations

      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. 

      Melphalan Pharmacokinetics

      Absorption

      The absorption of oral melphalan is highly variable with respect to both the time to first appearance of the drug in plasma (range: 0 to 6 hours) and peak plasma concentration (C). The average absolute bioavailability of melphalan is also highly variable (range: 56% to 93%). Oral administration of melphalan with a high fat meal may reduce melphalan exposure (AUC) by 36% to 54%.

      Distribution

      The steady-state volume of distribution of melphalan is 0.5 L/kg. The average melphalan binding to plasma proteins is highly variable (range: 53% to 92%).

      Elimination

      In 18 patients given a single oral dose of 0.6 mg/kg of Melphalan Tablets USP, the terminal elimination plasma half-life of parent drug was 1.5 ± 0.83 hours. The 24-hour urinary excretion of parent drug in these patients was 10% ± 4.5%, suggesting that renal clearance is not a major route of elimination of parent drug. In a separate study in 18 patients given single oral doses of 0.2 mg/kg to 0.25 mg/kg of Melphalan Tablets USP, Cmax and plasma concentration-time curves (AUC), when dose adjusted to a dose of 14 mg, were (mean ± SD) 212 ± 74 ng/mL and 498 ± 137 ng•hr/mL, respectively. Elimination phase half-life in these patients was approximately 1 hour and the median half-life was 1 hour.  Melphalan is eliminated from plasma primarily by chemical hydrolysis to monohydroxymelphalan and dihydroxymelphalan.

      Melphalan Interactions

      Interactions

      Radiotherapy potentiates antineoplastic effect. For IV: caution with cyclosporine, cisplatin, BCNU, nalidixic acid.

      Melphalan Adverse Reactions

      Adverse Reactions

      Bone marrow suppression, GI upset, hepatic dysfunction, anemia, blood dyscrasias, secondary malignancies (eg, nonlymphocytic leukemia), rash, alopecia, pulmonary fibrosis, interstitial pneumonitis, gonadal toxicity (amenorrhea, infertility); hypersensitivity reactions, cardiac arrest (rare).

      Adverse Reactions

      • Hematologic: Bone marrow suppression leading to leukopenia, thrombocytopenia, and anemia. Irreversible bone marrow failure has been reported.

      • Gastrointestinal: Nausea, vomiting, diarrhea, oral ulceration. Hepatic disorders ranging from abnormal liver function tests to hepatitis and jaundice have been reported. Hepatic veno-occlusive disease has been reported.

      • Miscellaneous: Other reported adverse reactions include pulmonary fibrosis (including fatal outcomes) and interstitial pneumonitis, skin hypersensitivity, maculopapular rashes, vasculitis, alopecia, and hemolytic anemia. Allergic reactions have occurred.

      Melphalan Clinical Trials

      See Literature

      Melphalan Note

      Notes

      Formerly known under the brand name Alkeran.

      Melphalan Patient Counseling

      Patient Counseling

      Advise patients that major toxicities of melphalan tablets are related to bone marrow suppression, hypersensitivity reactions, gastrointestinal toxicity, and pulmonary toxicity.

      Advise patients that the major long-term toxicities are related to infertility and secondary malignancies.

      Do not take melphalan without close medical supervision. Advise patients to consult their health care provider if they experience skin rash, vasculitis, bleeding, fever, persistent cough, nausea, vomiting, amenorrhea, weight loss, or unusual lumps/masses.

      Advise women of childbearing potential to avoid becoming pregnant.

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