Melphalan

Melphalan is an antineoplastic/ alkylating agent belonging to the pharmacological class of nitrogen mustards.

The FDA has approved Melphalan for the treatment of ovarian carcinoma, uveal melanoma with incurable hepatic metastases, multiple myeloma, a form of blood cancer, and high-dose conditioning before hematopoietic stem cell transplantation in patients.

Melphalan is rapidly absorbed from the gastrointestinal tract and reduces exposure when administered high-fat meals. It penetrates minimally into the central nervous system and enters breast milk. Excretion occurs through faeces (20-50% orally, 6-21% intravenously) and urine (10% orally).

Melphalan's most common side effects include nausea, vomiting, and anaemia (low number of red blood cells).

The molecule is available in India, the United States, Canada, the United Kingdom, Italy, Australia, Germany, France, Belgium and Spain.

Melphalan is an antineoplastic/ alkylating agent belonging to the pharmacological class of nitrogen mustards.

It is thought to be absorbed by tumour cells through an active neutral amino acid route that leucine exhibits. Melphalan disrupts transcription and DNA synthesis by binding to guanine at its N7 position and creating interstrand cross-links in the DNA. Moreover, it can result in RNA, proteins, lipids and DNA-protein cross-linking lesions. Melphalan causes tumour cells to divide quickly while they are at rest.

Melphalan is available in the form of oral tablets and powder for injection.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

Powder for injection: To be administered parenterally, as applicable.

As the physician recommends, take the medication orally once daily, and it is to be taken on an empty stomach.

Melphalan can be used for the following health conditions:

• Plasma cells seen in the bone marrow are the source of multiple myeloma, a cancer. Plasma cells produce antibodies that helps in the body's defence against infection and illness.
• Progression of ovarian cancer
• Progression of breast cancer
• An illness known as polycythaemia vera causes your blood to contain more red blood cells. Blood clots result from this thickening of the blood. Headaches, vertigo, and dyspnea result from this condition.

In Ovarian cancer

Cancer that occurs in the female reproductive system (ovaries) is known as ovarian cancer. This kind of cancer can be lethal as well as being found highly late. It typically extends to the stomach and pelvis. Melphalan inhibits the growth and destroys cancer cells while also preventing their replication. Although the medication is beneficial, there are some unsettling side effects. Thus, reviewing the advantages and disadvantages with the physician is advisable. While receiving this medication, it is recommended to abstain from alcohol use and to be well-hydrated by drinking lots of water.

In Multiple myeloma

In multiple myeloma, the body accelerates bone destruction, making them weak, painful, and prone to fractures. Doctors may prescribe Melphalan, a crucial component alongside chemotherapy, to enhance survival rates. This medication eliminates cancer cells, inhibiting their growth and preventing their spread. Adhering to the doctor's instructions is vital for optimal results. If calcium levels are not elevated, supplements of calcium and Vitamin D3 might be recommended.

Melphalan is indicated for multiple myeloma, a type of cancer that affects plasma cells in bone marrow. It is also used in high-dose conditioning regimens prior to stem cell transplantation in patients with certain types of cancer, such as multiple myeloma, breast cancer, ovarian cancer, and certain types of lymphomas.

Orally: Melphalan is usually administered orally as a tablet, once daily, with or without food; adjust dosage according to patient response and severity of condition. It's advisable to swallow the tablets whole with a full glass of water. Patients should refrain from crushing or chewing the tablets.

Parenterally: Melphalan is typically administered intravenously as an infusion.

Individuals must adhere strictly to the prescribed dosage and administration schedule. Patients are also advised to consult their healthcare provider about the medication's benefits and potential side effects.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Melphalan is available in the form of oral tablets and powder for injection.

Dose Adjustment in Adult Patients:

Multiple myeloma

Standard dosing schedules:

Regimen 1: 0.15 mg/kg daily, divided into four doses, to be repeated every six weeks; this regimen is typically used with a corticosteroid.

Regimen 2: 6 mg once daily for two to three weeks, then a maximum of four weeks off while closely observing blood levels. WBC and platelet counts may rise to the point where a maintenance dose of 2 mg per day is administered. Various routines have been employed; consult comprehensive directions unique to each product. If needed, postpone or modify the dosage. To ensure that potentially therapeutic levels have been reached, the dosage may need to be gradually increased until myelosuppression is evident.

Breast cancer

Take 0.15 mg/kg or 6 mg/m2 for five days and repeat every six weeks. If bone marrow toxicity was noted, a dose reduction might be necessary.

Ovarian adenocarcinoma

Every 4–8 weeks, or as soon as the bone marrow has recovered, take 0.2 mg/kg daily for five days.

Polycythemia vera

Remission induction: 6–10 mg daily for 5–7 days, followed by 2-4 mg daily until the disease is adequately controlled. Maintenance: 2–6 mg once a week, with dosage adjustments based on blood counts and cautious haemoglobin control.

Adhering to a well-balanced diet rich in proteins, vitamins, and minerals is crucial during treatment to support overall health. Sustain proper weight through regular exercise and a healthy diet, incorporating leafy vegetables, citrus fruits, fatty fish, berries, yoghurt, apples, peaches, cauliflower, cabbage, broccoli, beans, and herbs. Ensure well-rested nights with optimal sleep. Refrain from smoking and alcohol consumption. Avoid fast food, fried items, processed meats, refined carbs, and added sugars. Patients should consult their healthcare provider for personalized dietary guidance, as specific restrictions may apply during Melphalan therapy.

The dietary restriction should be individualized as per patient requirements.

• Patients with conditions that have previously shown resistance to Melphalan should not be treated with this medication. Melphalan should not be administered to patients with hypersensitivity to the drug.
• Pregnancy and lactation.

Warnings

Melphalan should only be used under the supervision of qualified medical professionals who are knowledgeable about the drug's effects and potential side effects. The dosage should also be appropriately regulated.

Similar to other nitrogen mustard medications, a high dosage will significantly suppress the bone marrow. For the majority of patients, Melphalan's most serious side effect is bone marrow suppression. Accordingly, the platelet count, haemoglobin, white blood cell count, and differential should be carried out before the beginning of therapy and before every successive cycle of Melphalan. It is recommended to stop treatment altogether if thrombocytopenia and leukopenia do not improve enough in the blood counts. Regular blood counts are necessary to determine the ideal dosage and prevent toxicity. It is important to consider adjusting the dosage based on blood counts on the day of therapy and during the nadir.

Rarely, hypersensitivity reactions occurred, including anaphylaxis. These reactions have recurred in patients with an IV Melphalan hypersensitivity reaction, even after several rounds of treatment. It is not recommended to re-administer oral or IV Melphalan in the event of a hypersensitive response.

Melphalan suppresses ovarian activity in premenopausal women, which leads to amenorrhea in a considerable proportion of cases. There have also been reports of both reversible and irreversible inhibition of testosterone.

Precautions

In all instances considering Melphalan for chemotherapy, physicians must diligently evaluate its necessity and potential risks. Caution is vital for patients with compromised bone marrow from prior treatments. If the leukocyte count falls below 3,000 cells/mcL or the platelet count drops below 100,000 cells/mcL, Melphalan should be stopped until counts recover. Deciding whether to routinely reduce the dosage for renal insufficiency is challenging due to patient variability and minimal urinary excretion in those with normal renal function. Close observation is necessary for azotemia patients, enabling timely dosage adjustments.

It is best to avoid administering live vaccinations to people who are immunocompromised.

Avoid alcohol consumption while taking Melphalan.

Avoid use during breastfeeding.

It is not recommended during pregnancy.

Avoid smoking. Increase intake of nutrient-rich foods.

The adverse reactions related to Melphalan can be categorized as:

• Hematologic: The most frequent adverse event is the suppression of the bone marrow, which can result in anaemia, thrombocytopenia, and leukopenia. Even though bone marrow suppression is expected, it is typically reversible if Melphalan is removed early enough. On the other hand, reports of irreversible bone marrow failure exist.
• Gastrointestinal: Oral ulcers, vomiting, nausea, and diarrhoea can happen. There have been reports of hepatic problems ranging from abnormal liver function tests to clinical symptoms, including jaundice and hepatitis.
• Other: Additional adverse events that have been observed include hemolytic anaemia, skin hypersensitivity, maculopapular rashes, vasculitis, pulmonary fibrosis (with lethal consequences), and interstitial pneumonitis. Numerous treatment courses have resulted in allergic responses, such as urticaria, oedema, skin rashes, and, infrequently, anaphylaxis. Rare occurrences of cardiac arrest have also been linked to these accounts.

There are no known drug or drug interactions with oral Melphalan tablets.

The most common side effects of Melphalan include:

• Nausea
• Vomiting
• Stomatitis, or oral inflammation
• Anaemia (low number of red blood cells)
• Hair loss
• Elevated blood urea levels (in patients receiving treatment for myeloma and renal issues)
• Low blood platelets
• Diarrhea
• Decreased white blood cell count

•Pregnancy

Pregnancy Category D (FDA): Use in cases where no safer medication is available and life is in danger. Positive evidence of prenatal risk in humans.

If Melphalan is given to a pregnant woman, it could harm the fetus. Following intraperitoneal (18 mg/m2) and oral (6 to 18 mg/m2/day for ten days) treatment, Melphalan was found to be teratogenic and embryolethal in rats. The brain (underdevelopment, distortion, meningocele, encephalocele), the eye (anophthalmia, microphthalmos), the tail, and the jaw were among the malformations brought on by Melphalan, along with the hepatocele (exomphaly).

There aren't enough reliable, well-controlled research on expectant mothers. Patients should be informed of the possible risks to the fetus if they use this medication while pregnant or if they get pregnant while taking it. Women of childbearing potential are advised to avoid becoming pregnant.

•Nursing Mothers

It is unknown if this medication is eliminated in human milk. Melphalan should not be given to nursing mothers.

•Pediatric Use

As per the FDA, safety and effectiveness in the pediatric population have not been established.

•Geriatric Use

There were not enough participants in clinical trials using Melphalan Tablets who were 65 or older to assess whether their responses differed from those of younger patients.

The responses of older and younger patients have not been shown to differ from one another in other documented clinical experiences. Since reduced hepatic, renal, or cardiac function is more common in older patients and because of concurrent diseases or other pharmacological therapies, dose selection for these patients should generally be careful and begin at the low end of the dosing range.

Dose Adjustment in Kidney Impairment Patients:

Renal impairment: Dose reduction may be required.

Dose Adjustment in Hepatic Impairment Patients:

Patients with liver function disorders should take caution while administering Melphalan tablets because the drug is extensively metabolized in the liver.

Signs and Symptoms

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Melphalan.

Overconsumption of Melphalan could lead to vomiting, ulceration of the mouth, diarrhoea, and bleeding of the gastrointestinal tract. In severe cases, bone marrow suppression may occur.

Management

If Melphalan overdose is suspected, immediately seek medical attention. Provide supportive care, monitor vital signs, and implement symptomatic measures. There is no specific antidote; if necessary, closely monitor the blood picture and consider general supportive measures, including hematopoietic growth factors, blood product transfusions and antibiotics. Melphalan is non-dialyzable. In severe cases, consulting a poison control centre or a medical toxicologist can be beneficial for appropriate guidance and intervention.

Pharmacodynamics:

Melphalan exhibits myeloablative, immunosuppressive, and cytotoxic properties. Melphalan is considered leukemogenic in humans since it causes chromosomal abnormalities both in vitro and in vivo. Additionally, it suppresses bone marrow in a dose-limiting manner. When multiple myeloma patients receiving autologous stem cell transplantation were given Melphalan 100 mg/m2 for two days, their peak mean heart rate rose by 20 bpm from baseline.

Pharmacokinetics:

•Absorption: Melphalan exhibits variable absorption from the gastrointestinal tract, with reduced exposure when taken with a high-fat meal. The absolute bioavailability ranges from 56% to 93%, and the time to reach peak plasma concentration is approximately 0.5-2 hours.

•Distribution: Melphalan has limited penetration into the central nervous system and enters breast milk. The volume of distribution is about 35.5-185.7 L/m2, with plasma protein binding ranging from 50-92%.

•Metabolism: Metabolism occurs in the liver through hydrolysis, resulting in monohydroxymelphalan and dihydroxymelphalan.

• Poczta A, Rogalska A, Marczak A. Treatment of Multiple Myeloma and the Role of Melphalan in the Era of Modern Therapies-Current Research and Clinical Approaches. J Clin Med. 2021 Apr 23;10(9):1841. doi: 10.3390/jcm10091841. PMID: 33922721; PMCID: PMC8123041.
• Case DC Jr, Coleman M, Gottlieb A, McCarroll K. Phase I-II trial of high-dose melphalan in previously untreated stage III multiple myeloma: Cancer and Leukemia Group B study 8512. Cancer Invest. 1992;10(1):11-7. doi: 10.3109/07357909209032784. PMID: 1735010.
• Cooper MR, Dear K, McIntyre OR, Ozer H, Ellerton J, Canellos G, Bernhardt B, Duggan D, Faragher D, Schiffer C. A randomized clinical trial comparing melphalan/prednisone with or without interferon alfa-2b in newly diagnosed patients with multiple myeloma: a Cancer and Leukemia Group B study. J Clin Oncol. 1993 Jan;11(1):155-60. doi: 10.1200/JCO.1993.11.1.155. PMID: 8418228.
• Edwards CL, Herson J, Gershenson DM, Copeland LJ, Wharton JT. A prospective randomized clinical trial of melphalan and cis-platinum versus hexamethylmelamine, adriamycin, and cyclophosphamide in advanced ovarian cancer. Gynecol Oncol. 1983 Apr;15(2):261-77. doi: 10.1016/0090-8258(83)90082-3. PMID: 6403413.

• https://www.ncbi.nlm.nih.gov/books/NBK304320/
• KD Tripathi. [link]. Seventh Edition. New Delhi, India: Jaypee Brothers Medical Publishers; 2013: Page No 861
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217110s000lbl.pdf
• April Hazard Vallerand, Cynthia A. Sanoski. [link]. Sixteenth Edition. Philadelphia, China: F. A. Davis Company; 2019: Page No 810-812