Melphalan Injection - Indication, Dosage, Precautions, and Pharmacological Aspects

Drug Overview:

Multiple myeloma, a kind of bone marrow malignancy, is treated with Melphalan injection in patients who are unable to take the medication orally. In addition, Melphalan injection is used to get rid of malignant and bone marrow cells in patients with multiple myeloma to get them ready for a bone marrow transplant. The drug belongs to the alkylating agents. It delays or halts the development of cancer cells within the body. The drug got its approval for intravenous use from the Food and Drug Administration (FDA) in 1964.

Drug Group: Alkylating agents.

For Patients:

What Is Multiple Myeloma?

Plasma cells, a kind of white blood cells (WBCs) crucial to the immune system, are targeted in multiple myeloma, a rare form of blood cancer. These plasma cells, also known as B-cells, produce immunoglobulins, which are antibodies that support the body's immune response to infections.

In the case of multiple myeloma, healthy cells undergo aberrant cell transformation, which leads to the proliferation of abnormal cells that create M proteins, a kind of faulty antibody. The affected person's bones, kidneys, and body's capacity to create healthy blood cells (WBC, RBC, and platelet) are all damaged by this metamorphosis, which also triggers a number of medical issues and health concerns.

How Does Melphalan Work?

Alkylating agents are a group to which Melphalan injection belongs. It functions by reducing or halting the proliferation of cancer cells within the body.

What Is the Dosage of Melphalan?

Since the injection is provided in a medical setup, the dosage is decided by the doctor and infused by them.

What Are the Things to Inform the Doctor Before Taking Melphalan?

• One should let their doctor and chemist know about any allergies they have before taking Melphalan, especially if they have any Melphalan allergies or allergies to its components.

• Informing the doctor and chemist about any prescription and over-the-counter medications, vitamins, dietary supplements, and herbal items used or intended to be taken is vital.

• The doctor may decide against using Melphalan if it has already been used to treat cancer and the therapy failed.

• While on Melphalan, refrain from getting any vaccines without first visiting the doctor.

• Melphalan may interfere with a woman's regular menstrual cycle. It might either temporarily or permanently inhibit the generation of sperm in males. Melphalan may result in infertility, and both men and women must be informed of this. Melphalan can damage the developing fetus; pregnant or nursing women should inform their doctors. It is essential to utilize trustworthy birth control throughout and after chemotherapy. It is advised to avoid pregnancy or breastfeeding during the therapy.

How Is Melphalan Administered?

A doctor or nurse (any trained healthcare provider) will administer Melphalan injection intravenously (into a vein) as an infusion over the course of 15 to 30 minutes. The medication is available as a powder that must be combined with fluids. Melphalan injection is often administered to persons with multiple myeloma who are unable to take Melphalan orally once every two weeks for four doses and then once every four weeks for the remainder of the time that the doctor suggests to continue the therapy. Melphalan is often administered intravenously once a day for two days before bone marrow transplant to patients with multiple myeloma in order to eradicate cancer cells and bone marrow in preparation for the procedure.

If there are certain adverse effects, the doctor may need to postpone the therapy or change the dose. During the Melphalan therapy, it is crucial that the patient communicates with the doctor about how they are feeling.

What Are the Side Effects of Melphalan?

The injection of Melphalan may have negative consequences. If any of these symptoms are severe or do not go away, let the doctor know right away:

• Heartburn.

• Missed menstrual periods (in females).

• Stomach pain.

• Nausea.

• Hair loss.

• Vomiting.

• Sores in the mouth and throat.

• Changes in the sense of taste.

• Diarrhea.

• Constipation.

• Loss of appetite or weight.

Some adverse effects may be severe. If any of the below symptoms develop, get emergency medical attention or contact a doctor straight away.

• Shortness of breath.

• Unusual lumps or masses.

• Itching.

• Swelling of the face, tongue, or throat.

• Blurry vision.

• Yellowing of the skin or eyes.

• Dizziness, lightheadedness, or fainting.

• Rash.

• In the area where the drug was injected, the patient can have itching, redness, puffiness, swelling, discomfort, blisters, or sores (injection site reactions).

• Difficulty breathing or swallowing.

• Pale skin.

• Fast, irregular, or pounding heartbeat.

• Pain in the upper right part of the stomach.

• Dark-colored urine.

• Unusual tiredness or weakness.

Missed Dose:

It is essential that people take their medications as directed. If they can not make it to a scheduled visit, they should get in touch with their doctor or healthcare provider.

Overdose:

In case of overdosing, medical help is needed immediately. Look for the below-mentioned symptoms to identify a case of overdosing.

• Vomitus with blood.

• Extreme nausea and vomiting.

• Diarrhea.

• Diminished awareness.

• Seizures

• Sores in the throat and mouth.

• Bleeding and bruising.

• The presence of blood in the stool or the stool appears black.

Storage

Melphalan injections must only be maintained or used inside a hospital or clinic, and it is not appropriate for use elsewhere. Hence, it is not stored at home.

For Doctors

Indication:

• Multiple Myeloma - Conditioning Treatment - Melphalan injection is authorized and advised especially for use as a high-dose conditioning therapy prior to hematopoietic progenitor (stem) cell transplantation in patients with multiple myeloma.

• Multiple Myeloma - Palliative Treatment - When oral medication is considered unsuitable or inappropriate, Melphalan is advised to provide palliative care to individuals with multiple myeloma.

Dose:

• Injection - A single-dose vial contains 50 mg (milligrams) of Melphalan as a white to off-white lyophilized powder for reconstitution. The reconstituted solution is transparent and has a color spectrum from colorless to pale yellow. Each vial contains 50 mg of Melphalan-free base, which is the same as 56 mg of Melphalan hydrochloride.

Dosing Considerations:

• Dosage for Conditioning Treatment - Before performing autologous stem cell transplantation (ASCT) on Day 0, the recommended conditioning therapy dosage of Melphalan is 100 mg/m2 (milligrams per square meter) per day, provided intravenously over a 30-minute infusion on two consecutive days, namely on day three and day two. It is vital to note that the body surface area estimate for patients whose weight exceeds 130 percent of their ideal body weight should be based on their modified ideal body weight.

• Dosage for Palliative Treatment - Melphalan should be administered as a single intravenous infusion over a period of 15 to 20 minutes at a dosage of 16 mg/m2 as part of palliative care. For a total of four doses, this should be given at two-week intervals. Following satisfactory recovery from any possible toxicity, the treatment regimen should change to a four-week interval.

• Dosage for Renal Impairment - Dose adjustment is not needed for patients suffering from renal impairment in case of conditioning treatment. For palliative treatment, patients with renal impairment (BUN - blood urea nitrogen 30 milligrams per deciliter) should consider a dosage decrease of up to 50 percent.

What Are the Pharmacological Aspects of Melphalan Injection?

• Physical Properties of the Drug:

  • Drug Group - Alkylating drug.

  • Appearance - White to off-white powder.

  • Chemical Name - 4-[bis(2-chloroethyl)amino]-L-phenylalanine hydrochloride.

  • Empirical Formula - C13H18Cl2N2O2 • HCl.

  • Molecular Weight - 341.67.

  • Solubility - Soluble in 1 N HCl and methanol. Insoluble in water.

  • Components of the Drug - Each vial includes 2700 milligrams (mg) of Betadex Sulfobutyl Ether Sodium, NF, and 50 mg of Melphalan-free base, which is equivalent to 56 mg of Melphalan hydrochloride.

• Mechanism of Action: Melphalan is classified as an alkylating agent belonging to the bis chloroethyl amine type. The main cause of its cytotoxicity is its capacity to connect DNA interstrand. Its attachment to the N7 position of guanine in DNA molecules is most likely the cause of this cytotoxic impact. Melphalan, like other bifunctional alkylating drugs, is effective against a variety of tumor cells, regardless of whether they are resting or proliferating quickly.

• Pharmacodynamics: Analyses of the pharmacokinetic and pharmacodynamic effects of Melphalan injection on the heart were conducted. It was discovered that the patient’s heart rate-corrected QT intervals increased by an average of 8.0 milliseconds after taking Melphalan injection compared to baseline measurements. Furthermore, individuals who got 200 mg/m2 (milligrams per square meter) of Melphalan injection saw a rise in their heart rate, which was, on average, 7.5 beats per minute higher than the baseline heart rate.

• Pharmacokinetics

1. Absorption - There are two stages of absorption after injecting Melphalan. The first stage lasts for around 10 minutes and is rapid, while the second stage is slower and lasts for about 75 minutes. The rate at which the body can eliminate this medication from the blood varies but is normally between seven and nine milliliters per minute per kilogram (ml/min/kg) of body weight.

2. Distribution - Melphalan is transported throughout the body after entering the circulation. It can pass across cell membranes, including the blood-brain barrier. Its distribution may be impacted by the ability of Melphalan to attach to blood proteins, notably albumin ( 40 to 60 percent)

3. Metabolism - Melphalan is mostly removed from the plasma by chemical hydrolysis into inactive monohydroxy melphalan and dihydroxy melphalan.

4. Excretion - Melphalan and its metabolites are mostly eliminated through the kidneys. Both its unmodified form and its metabolites are eliminated in the urine.

Toxicity (Carcinogenesis and Mutagenesis):

Studies on the carcinogenicity of Melphalan injection in animals have yet to be comprehensive or well-conducted. The development of lung tumors and abdominal sarcomas, respectively, followed months of therapy and observation when Melphalan injections were administered directly into the abdominal cavity of rats and mice. In a different investigation, varying doses of Melphalan injection into the muscles of rats resulted in alterations to the chromosomal structure in the bone marrow cells. These results raise the possibility that Melphalan may have cancer-causing effects, but more thorough research is required to validate these dangers.

Clinical Studies (Safety and Efficacy):

The majority of adverse events associated with Melphalan injections were transient and tolerable, and no unexpected toxic effects were noticed. Melphalan injections indicated a high degree of safety and tolerability. All patients had myeloablation (the capacity of the bone marrow to generate blood cells, including red blood cells, white blood cells, and platelets, which are purposefully and thoroughly destroyed or suppressed. To remove existing bone marrow cells and get the patient ready for the engraftment of new, healthy stem cells or to get rid of malignant cells, this treatment is frequently used in conjunction with stem cell transplantation or high-dose chemotherapy) as a result of the high-dose treatment, which aided in the prompt and effective engraftment of neutrophils and platelets. Positive response rates were achieved by a sizeable majority of patients.

What Are the Contraindications of Melphalan Injection?

Anaphylactic response to Melphalan, a severe allergic reaction that can be lethal, has previously occurred.

Warnings and Precautions:

• Bone Marrow Suppression - Patients who get Melphalan injection as part of their treatment may have myeloablation, a condition where the bone marrow malfunctions. Before beginning this treatment, it is crucial to have stem cells ready. Until the bone marrow heals, doctors should monitor the patient's blood counts and treat any infections, anemia (low red blood cells), and low platelet levels. There is a greater likelihood of a significant decline in blood cell counts in individuals using Melphalan injection for symptom alleviation if their bone marrow has previously been harmed by radiation or prior chemotherapy or is currently recuperating from chemotherapy. Throughout therapy, doctors should often monitor the patient's blood levels and treat infections, bleeding, and symptomatic anemia (anemia that manifests as obvious symptoms).

• Gastrointestinal Toxicity - More than 50 percent of patients who take Melphalan injections as part of a conditioning regimen may experience nausea, vomiting, mucositis, and diarrhea. Use preventative antiemetic drugs. Give supportive treatment for mucositis, diarrhea, vomiting, and nausea. For individuals with severe mucositis, administer nutritional assistance and painkillers. Oral ulcers, diarrhea, and nausea are possible side effects for individuals receiving Melphalan as palliative care. Utilize preventative antiemetics. Give supportive treatment for mucositis, diarrhea, vomiting, and nausea.

• Hepatotoxicity - Following Melphalan therapy, hepatic problems ranging from abnormal liver function tests to clinical symptoms, including hepatitis and jaundice, have been observed. Additionally, hepatic veno-occlusive disease has been documented. Observe the biochemical parameters of the liver.

• Hypersensitivity - About two percent of individuals who received an IV Melphalan formulation experienced acute hypersensitivity responses, including anaphylaxis. The only possible symptoms are urticaria, pruritus, edema, and skin rashes. Some individuals may also have tachycardia, bronchospasm, dyspnea, and hypotension. Stop using the medication for severe hypersensitive responses.

• Secondary Malignancies - It has been demonstrated that Melphalan damages human chromatids or chromosomes. Patients with multiple myeloma who received chemotherapy regimens containing Melphalan have been reported to develop secondary cancers like myeloproliferative syndrome or acute leukemia. The potential danger of a subsequent malignancy must be weighed against the potential benefit of Melphalan treatment.

• Infertility - According to reports, Melphalan-based chemotherapy regimens can decrease ovarian function in premenopausal women, which causes chronic amenorrhea in about nine percent of cases. There have also been reports of reversible or permanent testicular suppression.

• Embryo-Fetal Toxicity - Melphalan can damage a fetus when given to a pregnant woman because of the way it works. Melphalan is teratogenic in rats. It targets actively dividing cells and is genotoxic. Encourage pregnant women to abstain from getting pregnant both during and after taking Melphalan. Inform the patient about the possible danger to the fetus if this medication is used during pregnancy or if the patient gets pregnant while using this medication.

What Are the Drug Interactions of Melphalan Injection?

There have been no official studies on drug interactions. It has been documented that individuals who received a single intravenous (IV) Melphalan dosage of 140 to 250 mg/m2 (milligrams per square meter) followed by typical oral Cyclosporine doses had significant renal impairment. Intravenous Melphalan usage may make it simpler for BCNU (a chemotherapy drug) to induce lung damage. Pediatric children are more likely to develop severe hemorrhagic necrotic enterocolitis when Nalidixic acid and IV Melphalan are administered concurrently.

Specific Considerations:

• Pregnancy - If Melphalan injection is administered to a pregnant woman, the fetus might suffer injury. Birth abnormalities or even the death of the embryo or fetus might result from this injury. When used during pregnancy, the active component in Melphalan has the potential to harm a person's chromosomes. Even at dosages lower than those normally used for treating humans, Melphalan harms developing embryos and results in birth abnormalities in rats when tested on them. Therefore, if a woman is considering receiving Melphalan therapy while pregnant, it is crucial to let the individual know about these possible hazards to the unborn child.

• Lactating Mothers - The presence of Melphalan in breast milk has not been established. It is advisable to forgo breastfeeding while using Melphalan injection since certain drugs can enter breast milk and could affect nursing babies. It is a measure to guarantee the infant's safety.

• Pediatric Population - Clinical trials did not involve children as subjects; hence, safety and efficacy have not been determined in pediatric patients.

• Geriatric Population - There were no significant variations in the safety or efficacy of Melphalan between older individuals (aged more than 65 and less than 75 years) and the younger ones. However, it was noticed that older individuals had a greater risk of developing a condition known as "engraftment syndrome.” As per a study, 28 percent (5 out of 18) of patients 65 and older experienced this problem compared to 7 percent (three out of 43) of individuals under 65. Engraftment syndrome is a medical disease that can develop after a bone marrow transplant and be more prevalent among older participants.

• Renal Impairment Patients - Kidney diseases do not necessitate lowering the dose or avoiding Melphalan injection for those receiving it as part of a preparatory (conditioning) therapy. It could be wise to lower the dose if someone is using Melphalan injection for pain relief, particularly if they have renal problems. Bone marrow issues have been reported in persons with high BUN (blood urea nitrogen) values (a test of renal function) of 30 mg/dL (milligrams per deciliter) or higher. Reduced risk of these major bone marrow problems later in treatment can be achieved by halving the intravenous (IV) Melphalan dosage.