Busulfan - Dosages, Indication, Side Effects, and Warnings

Overview

A drug treatment to kill the rapidly growing cells of cancer is chemotherapy. Such a chemotherapeutic drug is Busulfan. It is used to manage and treat a type of blood cancer known as chronic myelogenous leukemia, which affects the blood-forming cells of the bone marrow. It is also used to treat other types of cancer that require bone marrow or stem cell transplant and myelodysplastic syndromes, a group of blood disorders.

Busulfan is an alkylating agent that interferes with the cancer cell's DNA, sticks to the DNA strands, and prevents the cancer cells from dividing. Thus, Busulfan prevents the proliferation of tumor cells and their growth in the body. Busulfan has been used since 1959 and was approved by the FDA (Food and Drug Administration) in 1999. The drug is indicated for use with Cyclophosphamide before stem cell transplantation for patients with chronic myelogenous leukemia (as a part of the regime).

What Is Chronic Myelogenous Leukemia?

Chronic myelogenous leukemia or chronic myeloid leukemia is cancer that begins in the cells of the bone marrow that form the blood cells. The immature cells in the bone marrow that make the red blood cells (RBC), platelets, and white blood cells (other than the lymphocytes) undergo a genetic change. This results in the formation of the BCR-ABL gene that transforms these immature cells into cancerous cells leading to chronic myelogenous leukemia.

The cancerous cells proliferate, grow and build up in the bone marrow, enter the bloodstream, and settle in other body parts, such as the spleen. This type of cancer is chronic or slow-growing leukemia. However, it can transform into acute leukemia that is difficult to treat. Chronic myelogenous leukemia is usually seen in adults and is rare in children.

For Doctors

Indications

Busulfan is an alkylating antineoplastic agent. The Food and Drug Administration (FDA) has indicated Busulfan administration as a part of the regimen before bone marrow transplantation (allogeneic hematopoietic progenitor cell transplantation). It is used along with cyclophosphamide, specifically for chronic myelogenous leukemia patients.

Busulfan is also used for patients undergoing similar allogeneic hematopoietic progenitor cell transplantation but for other acute or chronic and benign or non-cancerous blood disorders such as inborn immune system errors, hemoglobinopathies, or congenital metabolic diseases.

Contraindications:

• Busulfan should not be administered to patients with a history of hypersensitivity to Busulfan or its components.

• Busulfan is a pregnancy category D medication. Therefore, it should not be administered to breastfeeding mothers and pregnant women.

What Is the Role of Busulfan in Treating Chronic Myelogenous Leukemia?

Busulfan is a chemotherapeutic alkylating antineoplastic agent. It works by substituting the alkyl groups on the cancer cell's DNA resulting in DNA intrastrand cross-linkages. As a result, Busulfan inhibits the transcription of the cancer cell's DNA into RNA, preventing protein synthesis. In addition, Busulfan also results in DNA-protein binding, disrupted cellular redox equilibrium, and increased oxidative stress in the cancerous cells. Thus, Busulfan administration prevents the growth and proliferation of the rapidly dividing tumor cells in the bone marrow.

Dosage and Administration of Busulfan:

Busulfan can be administered orally (tablets) or intravenously. Before the stem cell transplantation procedure, patients over 12 kilograms of weight can be given Busulfan every six hours for four days, along with Cyclophosphamide. Intravenous administration of Busulfan is preferable as oral administration has a sizable therapeutic variability among patients.

The steps included in Busulfan administration are:

• Pre-medication with anticonvulsants and antiemetics is necessary.

• Busulfan must be diluted and administered as an intravenous infusion. It is not advisable to administer intravenous bolus or push.

• The recommended dose for adults is 0.8 milligrams per kilogram of body weight administered intravenously through a central venous catheter. It must be given for four consecutive days slowly as a two-hour infusion every six hours (a total of 16 doses).

Warnings and Precautions

Busulfan may cause the following:

• Prolonged Myelosuppression: Busulfan causes prolonged severe myelosuppression. Bone marrow transplantation is necessary to prevent the life-threatening complications of prolonged myelosuppression.

• Seizures: Initiation of prophylactic anticonvulsant therapy before Busulfan administration is essential. Patients with a history of head trauma, seizures, or those taking epileptogenic drugs must be monitored carefully to prevent seizures.

• Hepatic Veno-Occlusive Disease: The patients administered Busulfan have an increased risk of developing the hepatic veno-occlusive disease. Thus monitoring their serum alkaline phosphatase, transaminases, and bilirubin on a daily basis is essential.

• Embryo-Fetal Toxicity: Busulfan can cause harm to the fetus. Thus the patients must be advised about the potential risks to the fetus and informed about various contraceptive methods to prevent pregnancy while on Busulfan.

• Cardiac Tamponade: High doses of oral Busulfan and Cyclophosphamide are known to cause cardiac tamponade in pediatric patients with thalassemia. Symptoms such as vomiting and abdominal pain often preceded the tamponade.

Adverse Reactions

• Myelosuppression.

• Nausea.

• Stomatitis.

• Vomiting.

• Anorexia.

• Diarrhea.

• Insomnia.

• Interstitial pulmonary fibrosis.

• Fever.

• Hypomagnesemia.

• Abdominal pain.

• Anxiety.

• Headache.

• Hyperglycemia.

• Hypokalemia.

• Intestinal mucosal damage.

• Alopecia.

• Pancytopenia.

• Anemia.

• Amenorrhea.

• Impaired spermatogenesis.

• Increased risk of malignancy.

• Hyperpigmentation.

• Wasting syndrome.

• Thrombocytopenia.

• Rare medullary aplasia.

Toxicity

Busulfan toxicity leads to hepatic venous-occlusive disease and acute and chronic graft-versus-host disease. Maintaining an AUC (area under the concentration-time curve) between 78 to 101 milligrams can help to decrease toxicity and increase the patient's chance of survival. The hepatic venous-occlusive disease can be treated with Defibrotide (an antithrombotic and antiplatelet agent). Acute and chronic graft-versus-host disease is usually managed with corticosteroids.

For Patients

Why Is Busulfan Prescribed?

Busulfan is a chemotherapy drug that acts as an alkylating agent to treat blood cancers such as chronic myelogenous leukemia and blood disorders. Though Busulfan does not cure cancer, it helps to control cancer by preventing the proliferation of cancerous cells. Thus, it helps to improve the patient's quality of life by slowing down or preventing the growth of cancer cells in the body.

How Does Busulfan Act On Chronic Myelogenous Leukemia?

Chronic myelogenous leukemia is a slow-growing cancer of the immature precursor cells in the bone marrow that form the blood cells, such as the red blood cells (RBC), platelets, and white blood cells (other than the lymphocytes). These bone marrow immature blood cells undergo a genetic change resulting in the formation of the cancer gene - BCR-ABL gene, that transforms these immature cells into cancerous cells leading to chronic myelogenous leukemia. In 1999, Busulfan was approved by the FDA (Food and Drug Administration) for treating blood cancer - chronic myeloid leukemia. It interferes with the cancer cell's DNA. The drug sticks to the DNA strands of the cancerous cells and prevents them from dividing. Thus, Busulfan prevents cancer cells' proliferation and growth in the body.

How Should Busulfan Be Used?

Busulfan is administered as tablets (for oral use) and as an intravenous medication (directly into the patient’s veins). Busulfan tablets are usually administered once a day. The treatment length depends on the cancer type, other drugs administered to the patient, and how their body responds to the drug. Busulfan tablets must be taken at around the same time daily as prescribed by the healthcare provider.

The patients must follow the directions on the prescription label. In case of doubts, the patients or their caregivers must seek help from their healthcare provider. Busulfan tablets must be taken as directed by the healthcare provider, and patients must only try to change or adjust the dosage with their doctor's consent. The healthcare providers usually prescribe and adjust the dose of the Busulfan tablets depending on the patient's response to treatment and any adverse effects that the patient experience.

One must discuss it with their health care provider before taking the tablets. Busulfan tablets are also administered to prepare the patient for a procedure known as bone marrow transplantation or stem cell transplantation. Before the procedure, Busulfan is administered in combination with other drugs to destroy the active and rapidly proliferating bone marrow cancer cells before the procedure.

What Are the Precautions to Be Followed Before Taking Busulfan?

Before taking Busulfan tablets, the patients must:

• Tell the healthcare provider if they are allergic to Busulfan or other medications.

• Tell their healthcare provider the medications that they take (prescription and nonprescription medications), including nutritional supplements, vitamins, and herbal products.

• Keep their healthcare providers informed about taking medications such as Acetaminophen, Clozapine, Cyclosporine, Itraconazole, medications for mental illness and nausea, Phenytoin, Meperidine, and other chemotherapy medications such as Bendamustine, Carmustine, Cyclophosphamide, Ifosfamide, Lomustine, Melphalan, Procarbazine, Temozolomide, and Thioguanine. The healthcare provider might alter or change the doses of the other medications and Busulfan tablets and carefully monitor the patients to look for possible drug interactions and side effects.

• Tell their healthcare provider if they have previously received treatment with other chemotherapy medications or radiation therapy.

• Inform their healthcare provider if they have a history of head injury or seizures.

• Be aware that Busulfan tablets may interfere with normal menstruation and period cycles in women. In men, Busulfan can reduce or stop sperm production.

• Keep their healthcare providers informed if they are pregnant or breastfeeding.

• Tell their healthcare provider if they have not responded to Busulfan treatment.

• Talk to their healthcare providers regarding birth-control measures before initiating treatment.

• Be aware that Busulfan may harm the baby if a woman becomes pregnant while taking Busulfan.

What Should One Do if They Forget a Dose?

If a person forgets a dose, they should take the missed dose immediately as soon as they remember. However, in case of a missed dose and almost time to take the next dose, they can skip the missed dose and take the next dose as per schedule. It is important to know that one should not take a double dose to compensate for a missed dose.

What Side Effects Can Busulfan Cause?

Busulfan may lead to several side effects. If patients notice long-lasting side effects, they should consult their healthcare provider regarding the drug's safety.

• Nausea.

• Diarrhea.

• Loss of weight.

• Loss of appetite.

• Constipation.

• Dry mouth.

• Sores (ulcers) in the mouth and throat.

• Headache.

• Difficulty falling asleep.

• Disturbed sleep or difficulty staying asleep.

• Unusual anxiousness.

• Dizziness.

• Swelling in any part of the body (especially of the face, arms, hands, feet, lower legs, or ankles).

• Chest pain.

• Muscle pain.

• Back pain.

• Joint pain.

• Skin rashes.

• Itching.

• Dry skin.

• Darkening of skin.

• Hair loss.

Patients must be aware that some side effects can make them critically ill. One must immediately call their healthcare provider in case of the following:

• Fever.

• Sore throat.

• Cough and congestion.

• Signs of infection.

• Unusual bleeding.

• Unusual bruising.

• Difficulty breathing.

• Seizures.

• Black, tarry stools.

• Red urine.

• Vision loss or changes in vision.

• Severe vomiting.

• Stomach pain.

Important Warnings

• Busulfan administration can cause ovarian failure. Young girls on Busulfan may not reach puberty. Thus, patients must discuss the facts about the infertility risk while taking Busulfan.

• Busulfan severely decreases the number of stem cells and blood cells in the bone marrow.

• The side effects of Busulfan may be amplified and more severe if Busulfan is taken along with other drugs that reduce the blood cell count.

• Busulfan may also increase the patient's risk of developing other cancers.

• Busulfan can be absorbed through the skin and lungs. Thus, pregnant women should not breathe the dust from the tablets and should not handle them, as they may harm the pregnancy.

• Busulfan can increase the risk of infections or worsen any underlying infectious disease.

• Patients taking Busulfan must avoid contacting people with transmittable infections, such as viral infections (like chicken pox or flu), or persons who have received live vaccinations.

• If a person taking Busulfan has been exposed to any infection, they should inform their healthcare provider and take the necessary measures to prevent infections.

The patients and caregivers must follow up with their healthcare provider and laboratory. Healthcare providers usually order laboratory tests to check the person's response to the treatment. If the blood count drops too low, the healthcare providers alter the dose of medication to ensure the blood count returns to normal. Again, following the instructions and taking the medication as directed is vital.

What Should One Know About the Storage and Disposal of Busulfan?

• Busulfan must be kept in the container it came in. It must be stored tightly closed and kept out of children's reach.

• It must be stored at room temperature. Care should be taken to store the drug away from excess moisture and heat.

• Leftover medications or unrequired tablets must be disposed of safely (to prevent pets and children from accidentally consuming them).

• The best way to dispose of Busulfan is by handing it over to medicine take-back programs available in the area.

• One must lock safety caps and store the tablets in a safe place (away from children's reach) to protect young kids from poisoning due to accidental consumption.

What to Do in Case of an Overdose?

Suppose a person takes more than the recommended dose of Busulfan, shows symptoms of overdose, has collapsed, has trouble breathing, or is unconscious. In that case, it is crucial to call for emergency medical care or to rush to the nearest emergency department.