Melphalan (Injection/Hepatic Delivery System) - Indication, Dosage, Precautions, and Pharmacological Aspects

Overview:

Melphalan (Injection/Hepatic Delivery System), a ground-breaking medication that includes Melphalan for injection within a Hepatic Delivery System, received FDA (Food and Drug Administration) clearance on August 14, 2023. Adult patients with uveal melanoma who arrive with unresectable hepatic metastases that affect less than 50 percent of the liver can now utilize this novel treatment with official approval. Additionally, it is allowed for individuals who do not have extrahepatic illness or whose extrahepatic disease is contained to a certain region, such as the lung, bone, lymph nodes, or subcutaneous tissues, and is treatable with resection or radiation therapy.

Drug Group:

Melphalan belongs to the pharmacological class known as alkylating agents and is the main constituent of Melphalan (Injection/Hepatic Delivery System).

Available Doses and Dosage Forms:

Melphalan for injections is available in five tiny, single-use glass vials that are transparent and compact. It contains 50 grams of dry powder, either white or pale yellow. Before usage, these vials are supposed to be combined with a liquid that is given along with them.

For Patients:

What Is Uveal Melanoma With Unresectable Hepatic Metastases?

A relatively uncommon cancer affecting the melanocytes in the eye is called uveal melanoma. Even though the main tumor is typically successfully treated with surgery or radiation, around half of people with uveal melanoma will develop metastatic illness, which is when the cancer spreads to another area of the body. About 90 percent of individuals will develop uveal melanoma in their liver, with less often occurring cases in the lungs and bones. Since metastatic uveal melanoma patients most frequently die from liver failure, treating liver metastases is crucial. When uveal melanoma spreads to the liver, the liver is frequently covered with several tiny nodules. Most patients can receive many treatments with the Melphalan injections (hepatic delivery system), which treat the whole liver.

How Does Melphalan (Injection/Hepatic Delivery System) Work?

Treatment for metastatic uveal melanoma with hepatic metastases involves Melphalan with a Hepatic Delivery System (kit-based). The kit uses a cutting-edge device delivery system called the Hepatic Delivery System (HDS) to directly give Melphalan, a long-accepted chemotherapy treatment, to the liver. By restricting the quantity of Melphalan that enters the rest of the body, the medication treats cancer by entering the liver directly, reducing toxicity and adverse effects.

Adult patients with uveal melanoma who have hepatic metastases that cannot be removed, which have spread to less than 50 percent of the liver, and who have no extrahepatic disease or extrahepatic disease that is only present in the bone, lymph nodes, subcutaneous tissues, or lung and which can be surgically removed or radiographically treated.

What Is the Dosage of Melphalan (Injection/Hepatic Delivery System)?

Melphalan is given by intravenous infusion directly into the hepatic artery, spaced a minimum of six to eight weeks apart from one another and up to six times during the duration of the treatment. The dose is calculated at 3 milligrams per kilogram (mg/kg) based on the patient's ideal body weight (IBW). It is crucial to remember that there is a 220-milligram limit for a single therapy session. It is important to emphasize that if the patient has any negative side effects while receiving therapy, the prescription dose may be changed or decreased. Please see the full prescribing information for detailed and precise dose recommendations.

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

The individual should inform the doctor if they are allergic to the drug, pregnant or planning to get pregnant, and about lactation.

How Is Melphalan (Injection/Hepatic Delivery System) Administered?

The Hepatic Delivery method (HDS) is a unique method the medical team uses while performing the Melphalan (Injection/Hepatic Delivery System)treatment on a patient. Catheters are tiny tubes that are introduced through the skin into an artery in the liver during this surgery. The liver is momentarily cut off from the body's blood supply by this. The liver is injected directly with a medication called Melphalan for around 30 minutes. A filter removes the Melphalan from the blood as it leaves the liver. The filtered blood is then reintroduced into the patient's body. Through this method, the medication is delivered to the liver directly, lessening its effects on the rest of the body.

What Are the Side Effects of Melphalan (Injection/Hepatic Delivery System)?

• Thrombocytopenia: A condition where there is a low count of platelets in the blood.

• Tiredness: Feeling unusually fatigued or lacking energy.

• Low Iron Levels: Having lower than normal levels of iron in the blood.

• Nausea: Feeling queasy or having the urge to vomit.

• Muscle and Bone Pain: Experiencing discomfort or soreness in muscles and bones.

• Low White Blood Cells: Having a reduced count of white blood cells in the blood.

• Abdominal Pain: Feeling pain or discomfort in the stomach area.

• Neutropenia: A condition characterized by a low count of a type of white blood cell called neutrophils.

• Vomiting: Discharging the contents of the stomach through the mouth.

• Increased Alanine Aminotransferase: Higher levels of this enzyme in the blood can indicate liver damage.

• Prolonged Activated Partial Thromboplastin Time: A prolonged time for blood to clot, which can indicate a bleeding disorder.

• Increased Aspartate Aminotransferase: Elevated levels of this enzyme in the blood are often a sign of liver or heart issues.

• Increased Blood Alkaline Phosphatase: Higher levels of this enzyme in the blood can indicate various health conditions.

• Difficulty Breathing: Struggling to breathe normally.

Overdose:

• Too much Melphalan administered intravenously (IV) can cause symptoms such as severe nausea, vomiting, loss of consciousness, seizures, muscular weakness, and other physical problems. In addition, high doses of Melphalan can harm the lining of the stomach and intestines, leading to issues including mouth sores, diarrhea, and gastrointestinal bleeding. Veno-occlusive disease, which can also induce harm to the liver, is one such disorder.

• Low sodium levels in the blood as a result of an excessive release of the hormone antidiuretic hormone by the body are another problem that can result from a Melphalan overdose. This might result in a number of issues.

• Melphalan can potentially damage the kidneys and result in adult respiratory distress syndrome, a dangerous lung condition.

• The biggest issue with Melphalan overdose is that it can seriously impair the bone marrow's ability to produce blood cells, which can be fatal. In the event of an overdose, doctors must constantly check blood levels for a number of weeks. Supportive care, blood transfusions, antibiotics, and growth hormones may all be used throughout the course of treatment to aid bone marrow recovery.

• Hemodialysis (blood purifying processes) or hemoperfusion (clean blood outside the body to remove toxins) do not significantly remove this medication from systemic plasma.

Storage:

Melphalan (Injection/Hepatic Delivery System) for injection, together with its 0.9 percent sodium chloride mixing solution, must be stored in a temperature-controlled environment that is kept between 20 degrees Celsius (°C) and 25 degrees Celsius (68 degrees Fahrenheit (°F) and 77 degrees Fahrenheit). If the temperature fluctuates between 15°C and 30°C (59°F and 86°F) for a small period of time, it is acceptable as long as it does not last too long. The Hepatic Delivery System components can be kept at typical room temperature. Melphalan in (Injection/Hepatic Delivery System) is a harmful medicine. In order to handle and dispose of it securely, you must adhere to certain guidelines. Keep Melphalan (Injection/Hepatic Delivery System) in its original box until you are ready to use it because it's light-sensitive.

For Doctors:

Indications:

Adult patients suffering from uveal melanoma with unresectable hepatic metastases involving less than 50 percent of the liver and no extrahepatic disease or extrahepatic disease restricted to the bone should receive Melphalan injection as a part of the hepatic delivery system (kit-based). The lung, lymph nodes, or subcutaneous tissues can all be removed or treated with radiation.

Dosing Considerations:

Those individuals who weigh 35 kilograms or more should only use Melphalan injection in the Hepatic Delivery System. This is because individuals who weigh less may have trouble getting the catheter inserted. The Melphalan injection in the kit is administered by inserting a needle into the hepatic artery. The instructions for the use manual should be referred to for the entire process. An individual can receive this injection every six to eight weeks but no more than six times. According to a precise calculation, a person should take Melphalan injection at a dosage of 3 milligrams for every kilogram of their optimum body weight. The maximum one should provide in a single dose is 220 milligrams.

Melphalan for Injection: The kit contains five single-dose, transparent glass injection vials containing 50 milligrams of lyophilized white to light yellow powder for reconstitution with the included diluents.

What Are the Pharmacological Aspects of Melphalan Injection?

Mechanism of Action:

Melphalan is categorized as a bis chloroethyl amine-type alkylating medication. It looks like the degree of interstrand cross-linking it creates with DNA (deoxyribonucleic acid), most likely via binding to the N7 position of guanine, is related to the cytotoxic effects it has. It is significant that Melphalan works against both dormant and actively proliferating tumor cells.

Pharmacodynamics:

It has not been thoroughly established how Melphalan exposure and response, as well as the timing of pharmacodynamic effects after Melphalan injection administration through the hepatic delivery system, relate to one another.

Pharmacokinetics:

The peak concentration of Melphalan, which is roughly 2.4 micrograms per milliliter, is reached in the blood 0.57 hours after the medication is first taken. Melphalan is present in the blood at an average value of 1.8 micrograms per hour per milliliter. Keep in mind that these values might vary depending on the person.

• Distribution - When given as Melphalan injection as a part of the hepatic delivery system, Melphalan binds to plasma proteins at a degree of around 78 percent. Serum albumin (40 percent to 60 percent) and alpha 1-acid glycoprotein (20 to 25 percent) are primarily responsible for this binding. The distribution and accessibility of Melphalan in circulation are significantly influenced by these proteins.

• Elimination - With intravenous Melphalan administration, the median terminal elimination half-life of 1.07 hours was recorded, which shows the relatively quick removal of the drug from the body. This fast metabolism and quick excretion of melphalan is significant for dosage considerations and controlling its therapeutic effects.

• Metabolism - Melphalan metabolites that are inactive are predominantly produced via hydrolysis.

• Excretion - Following Melphalan injection delivery, two main processes help to reduce systemic Melphalan levels: Hepatic absorption and elimination by hepatic venous blood isolation and filtration through HDS (Hemodialysis-like System). Throughout the whole filtering period, HDS showed an average filter effectiveness of 82.7 percent (with a standard variation of 14.4 percent). Furthermore, both the parent medication and its metabolites are excreted by the kidneys in order to eliminate melphalan. All of these procedures help control Melphalan exposure in the body.

Toxicity:

Melphalan has not been fully studied for carcinogenicity in animals, which examines if a drug might cause cancer. The development of peritoneal sarcoma and lung tumors, respectively, in rats and mice after six months of therapy when Melphalan was injected directly into the abdominal cavity, followed by a further 12 months of observation of the animals. The chromosome and chromatid structures in the bone marrow cells of rats were altered after Melphalan was injected into their muscles at two different dosages. The potential for Melphalan to induce cancer or genetic harm is suggested by these data, but further study is required to validate this.

Clinical Studies (Safety and Efficacy):

Metastatic uveal melanoma, a kind of cancer that had primarily progressed to participants' livers, was the cancer type they were studying. The most deadly component of these people's cancer was in their liver, while some of them also had cancer in their bones, skin, lymph nodes, or lungs. A little over 56 percent of those in the research had never before taken any type of medication for cancer that had spread throughout their bodies.

91 patients with metastatic uveal melanoma, a kind of cancer that has migrated to the liver and cannot be surgically removed, were given the Melphalan (Injection/Hepatic Delivery System). For a maximum of six treatments, they got the kit every six to eight weeks. The results are as follows:

• The Objective Response Rate (ORR) - It is the proportion of patients whose tumors significantly shrank or vanished after treatment. 36.3 percent of the participants in this research saw this favorable outcome.

• The Duration of the Favorable Response (Lower Tumor Size or Elimination) - It is indicated by the DoR. For these individuals, it lasted an average of 14 months.

• The Disease Control Rate (DCR) -It is the proportion of patients whose tumors shrank or remained the same size. This was experienced by 73.6 percent of the participants in this trial, indicating some degree of cancer control.

• Full Responses (CR) And Partial Responses (PR) - 7.7 percent of patients saw a full tumor regression, whereas 28.6 percent of patients experienced a tumor size reduction.

What Are the Contraindications of Melphalan Injection as a Hepatic Delivery System (Kit-Based)?

• Active intracranial metastases or bleeding-prone brain lesions.

• Liver disease, portal hypertension, or known bleeding varices.

• Surgery or medical treatment of the liver in the previous four weeks before starting the drug.

• When general anesthesia is unsafe due to active heart problems.

• Allergy or hypersensitivity history to Melphalan.

• Coagulopathy, which is incurable.

• Allergies or known hypersensitivity to a component or substance used in the Melphalan Injection as a hepatic delivery system (Kit-Based).

REMS (Risk Evaluation and Mitigation Strategies) For Melphalan Injection as Part of the Hepatic Delivery System (Kit-Based)

There are severe hazards associated with Melphalan injection in the hepatic delivery system (kit-based), including bleeding, liver damage, and problems with blood clotting when it is being administered. There are stringent regulations in place to ensure that it is used safely.

• It is only usable by licensed healthcare professionals. They have received specialized training to manage this therapy.

• Facilities that provide the kit-based Melphalan injection therapy must abide by specific guidelines. They must enroll, obtain a certification, and abide by the safety regulations.

• Only facilities that have been certified by the program are permitted to provide patients with the kit-based Melphalan injection.

• Patients must be closely monitored for any serious issues that could arise as a result of the therapy both during the operation and for at least 72 hours following.

Warnings and Precautions:

Peri-Procedural Complications:

• Melphalan injections have been associated with issues like bleeding, liver cell destruction, and blood clots spreading to other regions of the body when administered directly into the hepatic artery. The patient must be under general anesthesia and have their blood temporarily redirected outside of their body in order to utilize the injections successfully; this can be extremely dangerous and even fatal.

• Make sure the patient is receiving the proper amount of fluids, but avoid giving them too much. Keep a watchful eye out for these issues both during the surgery and for at least 72 hours following it.

• Give the patient blood-thinning medicine as directed in the official instructions, or IFU (Instructions for Use), throughout the procedure to reduce the danger of blood clots.

• Bleeding Risk - Patients with serious, incurable bleeding issues should not receive Melphalan injections. One should wait at least four weeks before beginning this treatment after liver surgery or a comparable procedure since it may damage your blood's capacity to clot. As per the recommendations, one should monitor their blood platelets and clotting components. There are procedures to halt the anticoagulation and address the bleeding problem if there is significant bleeding while receiving therapy. Warfarin and other blood thinners should be stopped before the surgery and restarted once the danger of bleeding has decreased.

• Platelet Function - Stop taking Aspirin and nonsteroidal anti-inflammatory medications (NSAIDs) a week before the surgery since they may alter the function of the blood platelets.

• Liver and Biliary Anatomy - Some patients may be more susceptible to difficulties during the surgery if they have certain liver or bile duct problems. Doctors should review their medical history and keep a close eye out for complications following therapy.

• Blood Pressure Decrease - This operation may cause a significant drop in blood pressure. Doctors will keep a tight eye on the blood pressure. For the patient to elevate blood pressure, fluids and medications may be required. Some other blood pressure drugs may need to be temporarily stopped prior to the therapy in order to reduce the risk of extremely low blood pressure.

Myelosuppression: In individuals receiving Melphalan injection as a part of a hepatic delivery system (kit-based), hematologic side effects such as thrombocytopenia, anemia, and neutropenia have been seen. People with a history of chemotherapy, bone irradiation, or impaired bone marrow function are more likely to experience these effects. It is essential to keep a close eye out for serious infections, bleeding, and symptomatic anemia. Only patients with hemoglobin levels greater than 10.0 g/dL (gram per deciliter), platelet counts greater than 100,000 per microliter, and neutrophil counts greater than 2,000 per microliter should receive Melphalan injection. When required, transfusions and growth factors should be thought of as suitable therapies.

Hypersensitivity Reaction: Two percent of patients who received intravenous (IV) Melphalan have experienced hypersensitivity responses, including anaphylaxis. Urticaria, pruritus, edema, skin rashes, and, sometimes, tachycardia, bronchospasm, dyspnea, and hypotension are symptoms that define these responses. Patients with or without past IV or oral Melphalan exposure can develop hypersensitivity. If a hypersensitive reaction is seen when administering hepatic arterial Melphalan injection, it is critical to stop the infusion right once and administer any required supportive treatment. The Melphalan injection may cause hypersensitivity events, including anaphylaxis, in patients who have previously had allergic reactions to iodinated contrast. Patients who have previously experienced adverse responses to iodinated contrast should thus get premedication prior to receiving Melphalan injection.

Gastrointestinal Adverse Reactions: In the FOCUS study, 84 percent of patients using Melphalan injection had common gastrointestinal side symptoms such as nausea, vomiting, abdominal discomfort, and diarrhea. It is advised to provide a proton pump inhibitor the night before and the morning of the surgery to lessen these effects. Consider utilizing antiemetic medication in subsequent treatment cycles if nausea or vomiting are persistent.

Secondary Malignancies: It has been shown that Melphalan causes chromatid or chromosomal damage in people. Patients with cancer who received intravenous alkylating medications, such as Melphalan, have been reported to develop secondary malignancies such as acute nonlymphocytic leukemia, myeloproliferative syndrome, and carcinoma. Patients occasionally additionally received radiation therapy or other chemotherapy drugs. It is difficult to accurately quantify the risk for these secondary cancers. The chance of acquiring leukemia or other associated conditions may, however, increase with continued therapy and cumulative Melphalan dose, according to published data.

Embryo-Fetal Toxicity: Melphalan has the potential to damage fetuses when given to pregnant women, according to animal studies and its mode of action. Rat embryo lethality and teratogenic effects result from its genotoxic nature, which mostly damages cells that are actively proliferating. The possible hazards to the fetus must thus be made clear to pregnant mothers. It is advised for females of reproductive age to utilize reliable contraception during their Melphalan injection therapy and for six months following the last dosage. Similar to females, guys with female partners who may get pregnant should use reliable contraception while taking Melphalan injections and for three months afterward.

Infertility - Melphalan-containing chemotherapy regimens can have an impact on a woman's ovaries prior to menopause. Amenorrhea, a disorder when menstruation ceases, can result from this and affects roughly nine percent of patients for an extended period of time. It can also decrease the function of the testicles in males either momentarily or permanently.

Specific Considerations:

• Pregnancy - Pregnant women who take Melphalan run the risk of damage to the developing fetus. Before beginning Melphalan injection as the hepatic delivery system (kit-based) therapy, it is critical to check the pregnant status of females who are capable of reproducing.

  • Contraception:

    • Females - It is advised that females who are sexually active utilize reliable contraception during their Melphalan injection as the hepatic delivery system (kit-based) therapy and for six months following their last dosage.

    • Males - Melphalan injection as the hepatic delivery system (kit-based) dosing in men may harm spermatozoa and testicular tissue, perhaps resulting in genetic problems in the developing fetus. Males who have female partners who might get pregnant should thus use reliable contraception while taking Melphalan injection as the hepatic delivery system (kit-based) and for three months after the final dosage.

  • Infertility:

    • Females - Melphalan can cause the suppression of ovarian function in females, which frequently causes amenorrhea in a sizable portion of patients

    • Males - Following Melphalan treatment, reports of both reversible and irreversible testicular suppression in males have been seen.

• Lactating Mothers - Melphalan may or may not be present in human breast milk. It is advised to stop breastfeeding during Melphalan therapy and for one week following the last dosage since many medications can pass into breast milk and because Melphalan exposure in nursing infants may have major negative consequences.

• Pediatric Population - Melphalan injection as the hepatic delivery system (kit-based) has not been proven to be safe or beneficial in pediatric patients.

• Geriatric Population - It is difficult to determine if older patients' responses to the medication differ from those of younger subjects because persons 65 and older were not well represented in the clinical trials for Melphalan injection as the hepatic delivery system (kit-based). Only 30 out of the 91 patients in the FOCUS study were 65 years of age or older or around 33 percent of the total.