Melphalan – Uses, Dosage, Side Effects, Interactions

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.

Contraindications

• are allergic to melphalan or any ingredients of this medication
• are allergic to chlorambucil
• are breast-feeding
• are currently receiving radiation treatment
• have cancer that has shown resistance to melphalan in the past
• have a low count of neutrophils (a type of white blood cell)
• have a low platelet? count
• have received similar chemotherapy? medications or radiation treatments recently
• Melphalan hypersensitivity, risk of serious hypersensitivity reactions or anaphylaxis?.
• New primary malignancy.
• Anemia?, bleeding, bone marrow? suppression, infection?, leukopenia?, neutropenia?, and radiation therapy?, requires an experienced clinician, and thrombocytopenia?.
• Extravasation.

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 oral 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/ml. 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

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
• Oral: For the palliative treatment multiple myeloma.
• IV: For the palliative treatment 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

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
• sores in the mouth and throat
• black, tarry, or bloody stools
• bloody vomit or vomited material that looks like coffee grounds
• unusual bruising or bleeding
• sore throat, cough, fever, or other signs of infection

More Common

• loss of appetite
• loss of menses (women)
• mild pain or irritation at injection site
• nausea and vomiting
• diarrhea
• difficulty in swallowing
• mouth ulcers or sores
• redness and/or soreness in the arm or leg
• signs of bleeding (e.g., bloody nose, blood in urine or stools, coughing blood, cuts that don’t stop bleeding, unusual bleeding or bruising, or black, tarry stools)

Rare

• signs of decreased red blood cells (anemia; e.g., pale skin, fatigue, shortness of breath, rapid heartbeat)
• signs of infection (e.g., cough, fever, chills, severe diarrhea, shortness of breath, prolonged dizziness, headache, stiff neck, weight loss, or listlessness)
• signs of liver problems (e.g., nausea, vomiting, diarrhea, loss of appetite, weight loss, yellowing of the skin or whites of the eyes, dark urine, pale stools)
• sign of lung problems (e.g., sudden or worsening shortness of breath, wheezing, tiredness, fever, painful breathing)
• signs of urinary tract infection (e.g., frequent urge to urinate, bloody or cloudy urine, pain with urination)
• skin rash or itching
• sores in the mouth or on the lips
• swelling of feet or lower legs
• symptoms of compartment syndrome (e.g., pain, pale skin, numbness, tingling, weakness, or paralysis in the limb with the infusion site)
• fast or irregular heartbeat
• symptoms of a serious allergic reaction such as hives; difficulty breathing; or swelling of the eyelids, throat, and mouth
• symptoms of an injection site reaction (e.g., severe muscle or nerve damage, pain, tenderness and inflammation, ulcers, or infection at the injection site)

Drug Interaction

Pregnancy and Lactation

Pregnancy

There is a possibility of birth defects if either the man or the woman is taking melphalan at the time of conception, or if it is taken during pregnancy. Effective birth control should be practiced while using this medication. There may be an increased risk of blood clots for women using hormonal birth control while taking melphalan. Talk to your doctor about alternative options. Men who are taking this medication should not father a child during treatment and for 6 months after treatment is completed.

This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately.

Breast-feeding

It is not known if this medication passes into breast milk. If you are a breastfeeding mother and are taking melphalan, it may affect your baby. Talk to your doctor about whether you should continue breastfeeding. Patients should avoid breastfeeding during melphalan therapy because of the potential for serious adverse reactions in nursing children from melphalan. It is not known if melphalan is excreted into human milk. Do not resume breastfeeding until 1 week after the last melphalan dose.

 Warnings for this medication?

Before you begin using a medication, be sure to inform your doctor of any medical conditions or allergies you may have, any medications you are taking, whether you are pregnant or breastfeeding, and any other significant facts about your health. These factors may affect how you should use this medication.

Anemia: Melphalan may cause low levels of red blood cells. If you experience symptoms of reduced red blood cell count (anemia) such as shortness of breath, feeling unusually tired, or pale skin, contact your doctor as soon as possible.

Bleeding: This medication can reduce the number of platelet cells in the blood. Platelets help the blood to clot, and a shortage could make you bleed more easily. Tell your doctor of any signs that your blood is not clotting as quickly. Such symptoms may include black and tarry stools, blood in the urine, easy bruising, or cuts that won’t stop bleeding.

Blood clots: There may be an increased risk of blood clots in the legs or lungs when melphalan is used in combination with certain other medications. If you are at increased risk of blood clots, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.

Fertility: Sterility may occur with the use of melphalan.

Gout: This medication may cause high levels of uric acid in the blood, making gout more likely to occur.

Infection and vaccines: As well as killing cancer cells, this medication can reduce the number of cells that fight infection in the body (white blood cells). Avoid contact with people with contagious infections and tell your doctor if you begin to notice the signs of an infection such as fever or chills. Also tell your doctor if you have been vaccinated, or are planning to be vaccinated with a live vaccine.

Kidney problems: Kidney disease or reduced kidney function may cause this medication to build up in the body, increasing the risk of side effects. If you have kidney problems, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.

Lung problems: In rare cases, melphalan can cause lung problems (pulmonary fibrosis, permanent scarring of the lungs or interstitial pneumonitis, inflammation of the lungs) that, in some cases, can be fatal. If you experience any difficulty breathing, wheezing, fever, shortness of breath, cough, or coughing up of blood, accompanied by weakness and weight loss while taking melphalan, tell your doctor immediately.

Secondary cancer: When used for long periods of time, this medication can increase the risk of developing leukemia. If you have any concerns, talk to your doctor about the risks and benefits of using this medication.

Children: The safety and effectiveness of this medication have not been established for children.

When to contact your doctor or health care provider:

Seek emergency help immediately and notify your healthcare provider, it you experience the following symptoms:

• Shortness of breath, wheezing, difficulty breathing, closing up of the throat, swelling of facial features, hives (possible allergic reaction).

Contact your healthcare provider immediately, day or night, if you should experience any of the following symptoms:

• Fever of 100.4° F (38° C) or higher, chills (possible signs of infection)

The following symptoms require medical attention but are not an emergency.  Contact your healthcare provider within 24 hours of noticing any of the following:

• Nausea (interferes with the ability to eat and is unrelieved with prescribed medication)
• Vomiting (vomiting more than 4-5 times in a 24-hour period)
• Diarrhea (4-6 episodes in a 24-hour period)
• Unusual bleeding or bruising
• Black or tarry stools, or blood in your stools or urine
• Extreme fatigue (unable to carry on self-care activities)
• Mouth sores (painful redness, swelling, or ulcers)
• Yellowing of the skin or eyes. Signs of infection such as redness or swelling, pain in swallowing, coughing up mucous, or painful urination.

Always inform your healthcare provider if you experience any unusual symptoms.

Precautions:

• Before starting melphalan treatment, make sure you tell your doctor about any other medications you are taking (including prescription, over-the-counter, vitamins, herbal remedies, etc.). Do not take aspirin, or products containing aspirin unless your doctor specifically permits this.
• Do not receive any kind of immunization or vaccination without your doctor’s approval while taking melphalan.
• Inform your healthcare professional if you are pregnant or may be pregnant prior to starting this treatment.  Pregnancy category D (melphalan may be hazardous to the fetus.  Women who are pregnant or become pregnant must be advised of the potential hazard to the fetus).
• For both men and women: Do not conceive a child (get pregnant) while taking melphalan. Barrier methods of contraception, such as condoms, are recommended. Discuss with your doctor when you may safely become pregnant or conceive a child after therapy.
• Do not breastfeed while taking this medication.

Self-Care Tips:

• If taking melphalan pills take them on an empty stomach 1 hour before or 2 hours after meals.
• Drink at least two to three quarts of fluid every 24 hours, unless you are instructed otherwise.
• You may be at risk of infection so try to avoid crowds or people with colds and those not feeling well, and report fever or any other signs of infection immediately to your healthcare provider.
• Wash your hands often.
• To help treat/prevent mouth sores, use a soft toothbrush, and rinse three times a day with 1/2 to 1 teaspoon of baking soda and/or 1/2 to 1 teaspoon of salt mixed with 8 ounces of water.
• Use an electric razor and a soft toothbrush to minimize bleeding.
• Avoid contact sports or activities that could cause injury.
• This medication when taken as pills causes little nausea.  But if you should experience nausea, take anti-nausea medications as prescribed by your doctor, and eat small frequent meals.  Sucking on lozenges and chewing gum may also help.
• Avoid sun exposure.  Wear SPF 15 (or higher) sunblock and protective clothing.
• In general, drinking alcoholic beverages should be kept to a minimum or avoided completely.  You should discuss this with your doctor.
• Get plenty of rest.
• Maintain good nutrition.
• If you experience symptoms or side effects, be sure to discuss them with your healthcare team.  They can prescribe medications and/or offer other suggestions that are effective in managing such problems.

References