Melphalan Hydrochloride – Uses, Dosage, Side Effects, Interaction

Melphalan Hydrochloride is a bifunctional alkylating agent and phenylalanine derivative of nitrogen mustard. Melphalan hydrochloride is converted into highly reactive ethylenimmonium intermediates that induce covalent guanine N7-N7 intra- and inter-crosslinks and alkylation of adenine N3 of DNA. This agent also alkylates RNA and protein structures. As a result RNA transcription and protein synthesis are inhibited, ultimately leading to cell growth arrest and/or death.

Use in Cancer

Melphalan hydrochloride is approved to treat:

• Multiple myeloma.
  • It is used for palliative treatment in patients who cannot take melphalan by mouth. This use is approved for the Alkeran and Evomela brands.
  • It is used as a conditioning treatment to prepare patients for a stem cell transplant. This use is approved for the Evomela brand.

Melphalan hydrochloride is also being studied in the treatment of other types of cancer.

Melphalan is also available in a tablet form. For more information, see the Drug Information Summary for Melphalan.

Contraindication?

• a bad infection?
• a type of blood disorder where the red blood cells burst called hemolytic anemia?
• decreased function of bone marrow?
• anemia
• decreased blood platelets
• low levels of white blood cells
• low levels of granulocytes, a type of white blood cell
• inflammation? of the blood vessels
• hepatic veno-occlusive disease, a type of liver disease
• bleeding
• a type of inflammation of the lung called interstitial pneumonitis
• a condition where there is formation of fibrous tissue in the lung called pulmonary fibrosis?
• damage to the liver and inflammation
• decreased kidney? function
• abnormal liver function tests
• pregnancy
• a patient who is producing milk and breastfeeding

Dosage?

Strengths: 2 mg; 50 mg

Multiple Myeloma

ORAL:
A typical oral dosage regimen is:

• 6 mg orally once daily; after 2 to 3 weeks therapy should be discontinued for up to 4 weeks and the blood count followed; when white blood cell and platelet? counts are rising, a maintenance dose of 2 mg daily may be instituted

Alternate Oral Regimens:

• Osserman and Takatsuki have used an initial course of 10 mg/day for 7 to 10 days. They report that maximal suppression of the leukocyte? and platelet counts occurs within 3 to 5 weeks and recovery within 4 to 8 weeks. Continuous orally maintenance therapy with 2 mg/day is instituted when the white blood cell count? is greater than 4000 cells/mcL and the platelet count is greater than 100,000 cells/mcL. The dosage is adjusted to between 1 and 3 mg/day depending on the hematological response. It is desirable to try to maintain a significant degree of bone marrow depression to keep the leukocyte count in the range of 3000 to 3500 cells/mcL.
• Hoogstraten et al have started therapy with 0.15 mg/kg/day for 7 days followed by a rest period of at least 14 days, but it may be up to 5 to 6 weeks. Maintenance therapy is started when the white blood cell and platelet counts are rising. The maintenance dose is 0.05 mg/kg/day or less and is adjusted according to the blood count.
• One study by Alexanian et al has shown that using this drug in combination with prednisone significantly improves the percentage of patients with multiple myeloma who achieve palliation. One regimen has been to administer courses of this drug at 0.25 mg/kg/day for 4 consecutive days (or, 0.2 mg/kg/day for 5 consecutive days) for a total dose of 1 mg/kg/course. These 4- to 5-day courses are then repeated every 4 to 6 weeks if the granulocyte and platelet count have returned to normal levels.
• The entire oral dose may be given at one time.
• Numerous oral regimes have been used. Scientific literature and/or institutional protocol should be consulted for further information.
• Oral administration of this drug results in variable absorption; dosage may need to be cautiously increased until myelosuppression is seen to ensure that therapeutic levels have been reached.
• The administration of this drug with prednisone is more effective than this drug as monotherapy. The combination is usually given on an intermittent basis, although the superiority of this technique over continuous therapy has not been established.
• Evidence suggests that one-third to one-half of the patients with multiple myeloma show a favorable response to administration of this drug.
• Experience with oral administration suggests that repeated courses should be given since improvement may continue slowly over many months, and the maximum benefit may be missed if therapy is abandoned prematurely.
• There is no general agreement that all the procedures recommended in the guidelines are necessary or appropriate.

IV (when oral therapy is not appropriate):

• 16 mg/m2 as a single IV infusion over 15 to 20 minutes every 2 weeks for 4 doses; then, after adequate recovery from toxicity, at 4-week intervals
• Evidence suggests that one-third to one-half of the patients with multiple myeloma show a favorable response to administration of this drug.
• Dose adjustment based on blood cell counts at the nadir and day of therapy should be considered.
• There is no general agreement that all the procedures recommended in the guidelines are necessary or appropriate.
• Consult local institutional guidelines for alternate dosing options.
• Oral: For the palliative treatment of multiple myeloma.
• IV: For the palliative treatment of multiple myeloma when oral therapy is not appropriate.

Ovarian Cancer

• Common regimen: 0.2 mg/kg orally daily for 5 days as a single course; courses are repeated every 4 to 5 weeks depending upon hematologic tolerance
• There is no general agreement that all the procedures recommended in the guidelines are necessary or appropriate.
• Consult local institutional guidelines for alternate dosing options.
• For the palliation of nonresectable epithelial carcinoma of the ovary.

Renal Dose Adjustments

• In patients with moderate to severe renal impairment, currently available pharmacokinetic data do not justify an absolute recommendation on dosage reduction to those patients, but it may be prudent to use a reduced dose initially.
• Patients with azotemia should be closely observed to make dosage reductions, if required, as soon as possible.

IV:
A reduction of up to 50% should be considered in patients with renal insufficiency (BUN greater than or equal to 30 mg/dL).

ORAL:
A recommendation as to whether 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 this drug 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.

or

• Adult: As melphalan hydrochloride: Upper extremity perfusions: 0.6-1 mg/kg. Lower extremity perfusions: 0.8-1.5 mg/kg (in melanoma) or 1-1.4 mg/kg (in sarcoma).
• Elderly: Initiate treatment at the lower end of the dosing range.

• Adult: As melphalan hydrochloride: 0.4 mg/kg (16 mg/m²) repeated at appropriate intervals (e.g. once every 4 weeks) provided there has been a recovery of the peripheral blood count during this period. A high-dose regimen: 100-200 mg/m², to be followed by hematopoietic stem cell rescue if doses are >140 mg/m². As melphalan flufenamide: In patients with relapsed or refractory multiple myeloma who have received ≥4 prior lines of therapy and whose disease is refractory to ≥1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody: 40 mg over 30 minutes on Day 1 of each 28-day treatment cycle, in combination with dexamethasone. Continue until disease progression or unacceptable toxicity. Dose reduction or modifications may be required according to individual safety or tolerability (refer to detailed product guidelines).
• Elderly: Initiate treatment at the lower end of the dosing range.

• Adult: As melphalan hydrochloride: Monotherapy: 1 mg/kg (approx 40 mg/m²) given at intervals of 4 weeks. In combination with other cytotoxic drugs: 0.3-0.4 mg/kg (12-16 mg/m²) at intervals of 4-6 weeks
• Elderly: Initiate treatment at the lower end of the dosing range.

• Child: As melphalan hydrochloride: High-dose regimen: 100-240 mg/m² (may be divided equally over 3 consecutive days) followed by hematopoietic stem cell rescue if doses are >140 mg/m².

• Adult: 0.2 mg/kg daily for 5 days, repeated every 4-8 weeks, or as soon as the bone marrow has recovered.
• Elderly: Initiate treatment at the lower end of the dosing range.

• Adult: 0.15 mg/kg or 6 mg/m² daily for 5 days, repeated every 6 weeks. Dose reduction may be needed if bone marrow toxicity was observed.
• Elderly: Initiate treatment at the lower end of the dosing range.

• Adult: Remission induction: 6-10 mg daily for 5-7 days, then 2-4 mg daily until satisfactory disease control is achieved. Maintenance: 2-6 mg once weekly, with careful hematological control and dosage adjustment based on blood counts.
• Elderly: Initiate treatment at the lower end of the dosing range.

Oral
Multiple myeloma

• Adult: Usual dosage regimens: Regimen 1: 0.15 mg/kg daily in divided doses for 4 days, repeated at 6-week intervals, usually in combination with a corticosteroid. Regimen 2: 6 mg once daily for 2-3 weeks, followed by up to 4 weeks rest with careful monitoring of blood counts. A maintenance dose of 2 mg daily may be given if WBC and platelet counts are rising. Several regimens have been used; refer to detailed product-specific guidelines. Delay or adjust dose if necessary. Dosage may need to be cautiously increased until myelosuppression is observed, to ensure that potentially therapeutic levels have been reached.
• Elderly: Initiate treatment at the lower end of the dosing range.

Side Effects

The Most Common

• nausea
• vomiting
• loss of appetite or weight
• sores in the mouth and throat
• missed menstrual periods (in girls and women)
• joint, muscle, or back pain
• rash
• hives
• itching
• difficulty breathing or swallowing
• pale skin
• excessive tiredness
• fainting
• fast, irregular, or pounding heartbeat
• yellowing of the skin or eyes
• pain in the upper right part of the stomach
• dark colored urine
• unusual lumps or masses

More Common

• low white blood cell counts–fever, chills, cough, pain or burning when you urinate.
• low red blood cells (anemia)–pale skin, unusual tiredness, feeling light-headed or short of breath, cold hands and feet;
• easy bruising, unusual bleeding, purple or red spots under your skin;
• sores or white patches in or around your mouth, trouble swallowing or talking, dry mouth, bad breath, altered sense of taste;
• severe ongoing nausea, vomiting, or diarrhea;
• new or worsening cough, fever, trouble breathing;
• unusual lumps or masses;
• missed menstrual periods;
• inflammation of your blood vessels–warmth or tingling, skin rash, fever, headache, body aches, night sweats, weight loss, feeling or weak or tired;
• liver problems–loss of appetite, stomach pain (upper right side), dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or
• low potassium level–leg cramps, constipation, irregular heartbeats, fluttering in your chest, increased thirst or urination, numbness or tingling, muscle weakness or limp feeling.
• low blood cell counts;
• mouth sores;
• tiredness;
• low potassium levels; or
• hair loss.

Rare

• Nausea
• Bone marrow suppression, including
• Decreased white blood cell count causing the increased risk of infection
• Decreased platelet count causing an increased risk of bleeding
• Severe allergic reactions
• Pulmonary fibrosis (scarring of lung tissue) including fatal outcomes (usually only with prolonged use)
• Hair loss
• Interstitial pneumonitis
• Rash
• Itching
• Irreversible bone marrow failure due to melphalan not being withdrawn early enough
• Cardiac arrest

Drug Interaction

Pregnancy and Lactation

US FDA pregnancy category: Not Assigned

Pregnancy

There are no animal studies to evaluate the risk of exposure to the mother or the unborn child. This drug is genotoxic and has shown to be toxic to actively dividing animal cells. This drug has the potential to be teratogenic and cause embryo-fetal lethality. Based on animal toxicology studies, this drug may impair fertility in males and cause irreversible testicular suppression. There are no controlled data in human pregnancy.

Lactation

This drug should not be used during breastfeeding and for at least 1 week following the last dose. The effects on the nursing infant and milk production are unknown.

References