Melphalan Tablets

• If you have an allergy to melphalan or any other part of this medicine (melphalan tablets).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are breast-feeding. Do not breast-feed while you take this medicine.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine (melphalan tablets) with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• You may have more chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu.
• You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
• Talk with your doctor before getting any vaccines. Use with this medicine (melphalan tablets) may either raise the chance of an infection or make the vaccine not work as well.
• If you have upset stomach, throwing up, loose stools (diarrhea), or are not hungry, talk with your doctor. There may be ways to lower these side effects.
• To help with mouth sores, use a soft toothbrush or cotton swabs and rinse the mouth. Do not use mouth rinses that have alcohol in them.
• If you are 65 or older, use this medicine with care. You could have more side effects.
• This medicine may cause the ovaries to not work. This may also cause menstrual periods to stop. Talk with the doctor.
• This medicine may affect fertility. Fertility problems may lead to not being able to get pregnant or father a child. In both men and women, this may go back to normal but sometimes it may not. Talk with your doctor.
• If you are a man and have sex with a female who could get pregnant, protect her from pregnancy during care and for some time after care ends. Use birth control that you can trust. Talk with your doctor to see how long to use birth control after you stop this medicine (melphalan tablets).
• If you are a man and your sex partner gets pregnant while you take this medicine or within several months after your last dose, call your doctor right away.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant.
• Use birth control that you can trust to prevent pregnancy during care and for some time after care ends. Talk with your doctor to see how long to use birth control after you stop this medicine (melphalan tablets).
• If you get pregnant while taking this medicine or within several months after the last dose, call your doctor right away.

Use this medicine (melphalan tablets) as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take on an empty stomach. Take 1 hour before or 2 hours after meals.
• Take this medicine at the same time of day.
• You will need to take special care when handling this medicine (melphalan tablets). Check with the doctor or pharmacist to see how to handle this medicine.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Loose stools (diarrhea).
• Hard stools (constipation).
• Hair loss.
• Upset stomach or throwing up.
• Stomach pain.
• Not hungry.
• Change in taste.
• Mouth irritation or mouth sores.
• Feeling tired or weak.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Melphalan, also known as L-phenylalanine mustard, phenylalanine mustard, L-PAM, or L-sarcolysin, is a phenylalanine derivative of nitrogen mustard. Melphalan is a bifunctional alkylating agent which is active against selective human neoplastic diseases. It is known chemically as 4-[bis(2-chloroethyl)amino]-L-phenylalanine. The molecular formula is C13H18Cl2N2O2 and the molecular weight is 305.20. The structural formula is:

Melphalan is the active L-isomer of the compound and was first synthesized in 1953 by Bergel and Stock; the D-isomer, known as medphalan, is less active against certain animal tumors, and the dose needed to produce effects on chromosomes is larger than that required with the L-isomer. The racemic (DL–) form is known as merphalan or sarcolysin.

Melphalan is practically insoluble in water and has a pKa1 of ∼2.5.

Melphalan is available in tablet form for oral administration. Each film-coated tablet contains 2 mg melphalan USP and the inactive ingredients microcrystalline cellulose, colloidal silicon dioxide, crospovidone, magnesium stearate, hypromellose, titanium dioxide, and polyethylene glycol.

Melphalan is an alkylating agent of the bischloroethylamine type. As a result, its cytotoxicity appears to be related to the extent of its interstrand cross-linking with DNA, probably by binding at the N7 position of guanine. Like other bifunctional alkylating agents, it is active against both resting and rapidly dividing tumor cells.

Pharmacokinetics: 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 (Cmax). The average absolute bioavailability of melphalan is also highly variable (range: 56% to 93%). These results may be due to incomplete intestinal absorption, a variable "first pass" hepatic metabolism, or to rapid hydrolysis. Oral administration of melphalan with a high fat meal may reduce melphalan exposure (AUC) by 36% to 54%.

In 18 patients given a single oral dose of 0.6 mg/kg of Melphalan Tablets USP, the terminal elimination plasma half-life (t1/2) 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 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 t½ in these patients was approximately 1 hour and the median tmax was 1 hour.

One study using universally labeled. 14C-melphalan, found substantially less radioactivity in the urine of patients given the drug by mouth (30% of administered dose in 9 days) than in the urine of those given it intravenously (35% to 65% in 7 days). Following either oral or IV administration, the pattern of label recovery was similar, with the majority being recovered in the first 24 hours. Following oral administration, peak radioactivity occurred in plasma at 2 hours and then disappeared with a half-life of approximately 160 hours. In 1 patient where parent drug (rather than just radiolabel) was determined, the melphalan half-disappearance time was 67 minutes. The steady-state volume of distribution of melphalan is 0.5 L/kg. Penetration into cerebrospinal fluid (CSF) is low. The average melphalan binding to plasma proteins is highly variable (range: 53% to 92%). Serum albumin is the major binding protein, accounting for approximately 40% to 60% of the plasma protein binding, while α1-acid glycoprotein accounts for about 20% of the plasma protein binding. Approximately 30% of melphalan is (covalently) irreversibly bound to plasma proteins. Interactions with immunoglobulins have been found to be negligible.

Melphalan is eliminated from plasma primarily by chemical hydrolysis to monohydroxymelphalan and dihydroxymelphalan. Aside from these hydrolysis products, no other melphalan metabolites have been observed in humans. Although the contribution of renal elimination to melphalan clearance appears to be low, one pharmacokinetic study showed a significant positive correlation between the elimination rate constant for melphalan and renal function and a significant negative correlation between renal function and the area under the plasma melphalan concentration/time curve.

Melphalan Tablets USP are indicated for the palliative treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary.

Multiple Myeloma: The usual oral dose is 6 mg (3 tablets) daily. The entire daily dose may be given at one time. The dose is adjusted, as required, on the basis of blood counts done at approximately weekly intervals. After 2 to 3 weeks of treatment, the drug should be discontinued for up to 4 weeks, during which time the blood count should be followed carefully. When the white blood cell and platelet counts are rising, a maintenance dose of 2 mg daily may be instituted. Because of the patient-to-patient variation in melphalan plasma levels following oral administration of the drug, several investigators have recommended that the dosage of Melphalan Tablets USP be cautiously escalated until some myelosuppression is observed in order to assure that potentially therapeutic levels of the drug have been reached.

Other dosage regimens have been used by various investigators. 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 maintenance therapy with 2 mg/day is instituted when the white blood cell count is greater than 4,000 cells/mcL and the platelet count is greater than 100,000 cells/mcL. Dosage is adjusted to between 1 and 3 mg/day depending upon the hematological response. It is desirable to try to maintain a significant degree of bone marrow depression so as to keep the leukocyte count in the range of 3,000 to 3,500 cells/mcL.

Hoogstraten et al have started treatment with 0.15 mg/kg/day for 7 days. This is followed by a rest period of at least 14 days, but it may be as long as 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.

Available evidence suggests that about one third to one half of the patients with multiple myeloma show a favorable response to oral administration of the drug.

One study by Alexanian et al has shown that the use of Melphalan Tablets USP in combination with prednisone significantly improves the percentage of patients with multiple myeloma who achieve palliation. One regimen has been to administer courses of Melphalan Tablets USP 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. These 4- to 5-day courses are then repeated every 4 to 6 weeks if the granulocyte count and the platelet count have returned to normal levels.

It is to be emphasized that response may be very gradual over many months; it is important that repeated courses or continuous therapy be given since improvement may continue slowly over many months, and the maximum benefit may be missed if treatment is abandoned too soon.

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.

Epithelial Ovarian Cancer: One commonly employed regimen for the treatment of ovarian carcinoma has been to administer Melphalan Tablets USP at a dose of 0.2 mg/kg daily for 5 days as a single course. Courses are repeated every 4 to 5 weeks depending upon hematologic tolerance.

Administration Precautions: Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. 1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.