Busulfan
Drug Related WarningBusulfan
- Bone marrow suppression is common; in cases of unusual suppression, lower the dosage or stop oral administration (a bone marrow biopsy may be required); hematopoietic progenitor cell transplantation is necessary to avoid potentially fatal consequences of prolonged myelosuppression.
- After administering these doses, monitoring is crucial.
- This medication should be used under a doctor's supervision who has experience with cancer chemotherapy.
Medicine Type :
Allopathy
Allopathy
Prescription Type:
Prescription Required
Prescription Required
Approval :
DCGI (Drugs Controller General of India)
DCGI (Drugs Controller General of India)
Schedule
Schedule H
Schedule H
Pharmacological Class:
Alkyl sulfonate, Therapy Class:
Antineoplastic agent, Alkalyting agent, Approved Countries
India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.
Busulfan is an antineoplastic and alkylating agent belonging to the pharmacological class of alkyl sulfonate.
FDA approves busulfan to treat chronic myelogenous leukaemia.
Busulfan rapidly absorbs in the gastrointestinal tract, displaying a 68-80% bioavailability, depending on age. It crosses the blood-brain barrier, binds mainly to albumin, undergoes extensive hepatic metabolism via glutathione conjugation, and is primarily excreted in urine.
The most common side effects of busulfan include decreased blood cells (red cells, white cells, and platelets), nausea, vomiting, and loss of appetite.
Busulfan is available as an injectable solution and tablets.
The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.
Busulfan is an antineoplastic and alkylating agent belonging to the pharmacological class of alkyl sulfonate.
The alkylating agent busulfan is made up of two labile methanesulfonate groups that are attached to opposite ends of a 4-carbon alkyl chain. Methanesulfonate groups break down, and carbonium ions are produced when busulfan hydrolyzes. These carbonium ions cause DNA to become alkylated, which obstructs DNA replication and RNA transcription and ultimately disrupts the function of nucleic acids. Guanine-adenine intrastrand crosslinks are produced explicitly by its mechanism of action, which involves alkylation. Guanine N7 nucleophilically targets the carbon adjacent to the mesylate, leaving the group in the SN2 reaction that creates these crosslinks. The cell goes through apoptosis because the cellular machinery cannot repair this damage.
The onset of action initiates within 1 to 2 weeks, remains effective for 24 hours, and reaches its highest concentration in the bloodstream at approximately 1 hour when taken orally and about 5 minutes when administered intravenously.
Busulfan is available as an injectable solution and tablets.
Tablet: To be swallowed whole with water/liquid. Do not chew, crush or break it.
Injectable solutions: To be administered parenterally as applicable. The physician recommends taking this medication orally once daily, with or without food.
Blood cancer (Chronic myeloid leukaemia)
Blood cancer (Chronic myeloid leukaemia): Busulfan inhibits the excessive production of abnormal white blood cells in Chronic Myeloid Leukemia (CML), reducing their proliferation and delaying the disease's progression. For people with Chronic Myeloid Leukemia, this medication offers beneficial results by slowing the progression of the disease, extending remission, and increasing survival rates. It successfully lowers the number of abnormal white blood cells, improving the body's defences against the illness and improving prognoses for those suffering from it.
For the treatment of chronic myelogenous leukaemia (CML), use in combination with cyclophosphamide during a conditioning regimen before allogeneic hematopoietic progenitor cell transplantation.
Orally: Typically, divided doses of busulfan tablets are taken orally at regular intervals. Without chewing or crushing the tablets, swallow them whole with water.
Parenterally: Administer busulfan intravenously through a central venous catheter as a 2-hour infusion, repeating every 6 hours for four consecutive days to complete 16 doses. Dilute the drug with a compatible intravenous solution and infuse over a specified duration. After infusion, thoroughly flush the intravenous line with a consistent solution to ensure complete administration and avoid residue. Avoid polycarbonate syringes and maintain aseptic techniques during preparation and administration to prevent infections.
The dosage and duration of treatment should be as per the treating physician's clinical judgment.
Injectable solution: 6mg/mL
Tablet: 2mg
Busulfan is available as an injectable solution and tablets.
Dose Adjustment in Adult Patients:
Chronic myeloid leukaemia (granulocytic, myelocytic, and myeloid)
Chronic myelogenous (granulocytic, myelocytic, and myeloid) A leukaemia
Use antiemetic drugs and anticonvulsants (such as benzodiazepines, phenytoin, valproic acid, or levetiracetam) as preventative measures.
Induction of remission: 60 mcg/kg/day or 1.8 mg/m^; standard range: 4–8 mg PO qDay
Maintenance doses: take 1-4 mg daily to 2 mg weekly PO to maintain WBC. When leukocyte count drops to about 15,000/mcL, 10,000–20,000 cells/mm³ may not administer medication.
Once the patient's total leukocyte count reaches 50,000/mcL, resume the induction dosage and perform monthly assessments.
Given in combination with cyclophosphamide at a dose of 0.8 mg/kg IV every six hours for four days until the WBC count reaches 15,000/mm³.
Administration: take on an empty stomach to reduce the chance of N/V
Follow dietary guidelines while taking busulfan for increased safety and treatment efficacy. Incorporate leafy greens, citrus fruits, fatty fish, berries, yoghurt, apples, peaches, cauliflower, cabbage, broccoli, beans, and herbs into your diet. Abstain from smoking and consuming alcohol. Minimize fast food intake, fried items, processed meats, refined carbohydrates, and added sugars to optimize the medication's effects and overall well-being.
The dietary restriction should be individualized as per patient requirements.
In patients with a history of hypersensitivity to any of its components.
Patients without a definitive diagnosis of CML
- Seizures: Start prophylactic anticonvulsant therapy before initiating Busulfan treatment. Monitor patients with a history of seizure disorder, head trauma, or those receiving epileptogenic drugs closely.
- Myelosuppression: Busulfan usage may result in myelosuppression. Regularly monitor blood counts for any abnormalities.
- Hepatic Veno-Occlusive Disease (HVOD): Increased risk of HVOD occurrence at AUC greater than 1,500 μM•min. Daily monitoring of serum transaminases, alkaline phosphatase, and bilirubin is essential.
- Embryo-Fetal Toxicity: Busulfan poses a risk of fetal harm. Advise individuals about potential fetal risks and recommend the use of effective contraception during treatment.
- Cardiac Tamponade: Pediatric patients with thalassemia who received high doses of oral busulfan and cyclophosphamide experienced cardiac tamponade. Preceding symptoms included abdominal pain and vomiting.
- Pulmonary Toxicity: Bronchopulmonary dysplasia with pulmonary fibrosis has been reported as potentially fatal. Discontinue therapy if busulfan toxicity manifests. Avoid concomitant use with agents causing pulmonary toxicity.
- Cellular Dysplasia: Busulfan may induce cellular dysplasia in various organs, presenting with giant, hyperchromatic nuclei in lymph nodes, pancreas, thyroid, adrenal glands, liver, lungs, and bone marrow. This may complicate cytologic examinations of the lungs, bladder, breast, and uterine cervix.
Alcohol Warning
It is unsafe to consume busulfan with alcohol.
Breast Feeding Warning
It is not recommended for use during breastfeeding.
Pregnancy Warning
It is not recommended for use during pregnancy.
Food Warning
Consume an antioxidant-rich diet, and avoid smoking/alcohol.
The adverse reactions related to busulfan can be categorized as:
Common Adverse Effects: Myelosuppression, involving a reduction in blood cell count, gastrointestinal disturbances such as nausea, vomiting, and diarrhea
Less Common Adverse Effects: Abdominal pain, confusion, seizures, and alterations in liver function, typically indicated by elevated liver enzymes
Rare Adverse Effects: Hepatic Veno-Occlusive Disease (HVOD), embryo-fetal toxicity, bronchopulmonary dysplasia accompanied by pulmonary fibrosis, cardiac tamponade, and cellular dysplasia
Reports on postmarketing
Neutropenia febrile
Syndrome of tumour lysis
Sepsis, severe fungal, bacterial, or viral infections (such as cytomegalovirus viremia)
Thrombotic micro-angiopathy (TMA)
Hypoplasia of teeth: Myelosuppression, involving a reduction in blood cell count, gastrointestinal disturbances such as nausea, vomiting, and diarrhea
Less Common Adverse Effects: Abdominal pain, confusion, seizures, and alterations in liver function, typically indicated by elevated liver enzymes
Rare Adverse Effects: Hepatic Veno-Occlusive Disease (HVOD), embryo-fetal toxicity, bronchopulmonary dysplasia accompanied by pulmonary fibrosis, cardiac tamponade, and cellular dysplasia
Reports on postmarketing
Neutropenia febrile
Syndrome of tumour lysis
Sepsis, severe fungal, bacterial, or viral infections (such as cytomegalovirus viremia)
Thrombotic micro-angiopathy (TMA)
Hypoplasia of teeth Abdominal pain, confusion, seizures, and alterations in liver function, typically indicated by elevated liver enzymes
Rare Adverse Effects: Hepatic Veno-Occlusive Disease (HVOD), embryo-fetal toxicity, bronchopulmonary dysplasia accompanied by pulmonary fibrosis, cardiac tamponade, and cellular dysplasia
Reports on postmarketing
Neutropenia febrile
Syndrome of tumour lysis
Sepsis, severe fungal, bacterial, or viral infections (such as cytomegalovirus viremia)
Thrombotic micro-angiopathy (TMA)
Hypoplasia of teeth
The clinically relevant drug interactions of busulfan are briefly summarized here.
- Drug-Drug Interactions: Busulfan interacts with immunomodulatory drugs (such as adalimumab and ozanimod), vaccines (such as the live influenza virus vaccine, dengue vaccine, and BCG vaccine), antipsychotic drugs (such as Clozapine), antirheumatic drugs (such as leflunomide), and medications used to treat moderate-to-severe plaque psoriasis (such as deucravacitinib).
- Drug-Food Interactions: When taking busulfan, avoid drinking alcohol or grapefruit juice. The way the medication functions may be altered.
- Drug-Disease Interactions: Busulfan may interact with several diseases, such as infections (bacterial, fungal, protozoal, or viral), myelosuppression (bone marrow depression/low blood counts, fever, bleeding), and severe renal and hepatic impairment.
The common side effects of busulfan include blood cell reduction (red cells, white cells, platelets), nausea, anaemia, bruising, bleeding gums, nosebleeds, abdominal pain, vomiting, loss of appetite, anxiety, infection risk, reduced magnesium and potassium levels, diarrhoea, fever, joint, back, or muscle pain, headache, elevated creatinine and glucose levels, insomnia, stomatitis (mouth inflammation).
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.
Can harm a fetus if given to her; drug proven to be teratogenic in mice, rats, and rabbits after administration during organogenesis; solvent, DMA, may also harm a fetus if given to a pregnant woman; in rats, DMA doses of about 40% of daily dose of DMA in dose on a mg/m² basis given during organogenesis caused significant developmental anomalies; no human data available informing drug-associated risk; Warn expectant mothers about possible fetal risks.
Advise women who are fertile to use effective contraception both during their treatment and for six months after it ends.
It may cause harm to testicular tissue and spermatozoa, potentially leading to genetic abnormalities in a fetus; men who have female partners who are fertile should use effective contraception while undergoing treatment and for three months after stopping it.
Infertility
Females: Premenopausal women receiving long-term, low-dose busulfan therapy for chronic myelogenous leukaemia often experience ovarian suppression and amenorrhea; the treatment may also result in transient or irreversible infertility in prepubertal girls or females of childbearing potential receiving high-dose busulfan as part of the conditioning regimen before allogeneic hematopoietic progenitor cell transplantation.
Men: Male patients have been reported to have testicular atrophy, azoospermia, and sterility.
Nursing Mothers
The presence of busulfan in human milk is unknown. Stop breastfeeding while taking busulfan because it may cause tumours in both human and animal studies. This is because many medications are excreted in human milk.
Pediatric Use
As per the FDA, busulfan's effectiveness in treating CML has not been specifically studied in pediatric patients.
Dose Adjustment
Geriatrics (> 65 years old) Use
The safety and efficacy of busulfan in the geriatric population have yet to be thoroughly established. Efficacy and safety in this group may vary, requiring cautious dosing and close monitoring for potential side effects. Further studies are needed to ascertain its optimal use and risk-benefit profile in older individuals.
Dose Adjustment
Prolonged Myelogenous Leukemia (Myeloid, Myelocytic, Granulocytic)
Remission induction: 4–8 mg PO qDay is the typical range; 60 mcg/kg/day or 1.8 mg/m²
Maintenance doses: 1-4 mg/day to 2 mg/week PO to maintain 10,000–20,000 cells/mm³ of WBC; medication may be stopped when the leukocyte count falls to about 15,000/mcL.
Examine the patient once a month, and when the total leukocyte count approaches 50,000/mcL, restart the induction dosage of treatment.
Administered as a component of busulfan/cyclophosphamide: 0.8 mg/kg IV every six hours for four days or until the WBC count reaches 15,000/mm³.
Administration: consume on an empty stomach to lower the risk of perforation.
Monitor: CBC, Hgb, and LFTs
Dose Adjustment in Kidney Impairment Patients:
Not studied.
Dose Adjustment in Hepatic Impairment Patients:
Unknown; for liver toxicity symptoms
The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of busulfan.
Signs and Symptoms
Overconsumption of Busulfan could lead to myelosuppression and pancytopenia.
Management
In the event of a Busulfan overdose, no specific antidote exists, necessitating symptomatic and supportive measures. Vital signs require close monitoring, frequent blood count assessments, and potential complication management, such as infections or myelosuppression. Inducing vomiting or employing gastric lavage, followed by charcoal administration for recent ingestion, may be advisable. Haemodialysis and glutathione administration could be considered. Monitor liver function and hepatic enzymes regularly. Prompt medical intervention is pivotal in managing Busulfan overdose, ensuring meticulous monitoring and appropriate care to address symptoms and avert complications.
Pharmacodynamics
The ability of busulfan, an alkylating agent, to add alkyl groups to various electronegative groups under conditions found in cells gives it its name. By directly attacking DNA, they crosslink guanine bases in double-helix strands to halt tumour growth. As a result, the strands are unable to uncoil and split. The cells are unable to divide because this is required for DNA replication. Additionally, these medications miscode DNA by adding methyl or other alkyl groups to molecules where they shouldn't be. Three distinct mechanisms are employed by alkylating agents, which are non-specific to the cell cycle and ultimately lead to DNA disruption and cellular death. Resistance to busulfan is conferred by overexpression of the glutathione s-transferase MGST2. MGST2's function in busulfan metabolism is unclear, though.
Pharmacokinetics:
Absorption: Busulfan is wholly and rapidly absorbed through the gastrointestinal tract. Its oral bioavailability ranges from 68-80% depending on age, with peak plasma concentration typically reached in about 1 hour after oral intake and within 5 minutes when administered intravenously (IV).
Distribution: The medication readily crosses the blood-brain barrier, entering the cerebrospinal fluid (CSF) at concentrations equivalent to plasma. The volume of distribution is approximately 0.64 ± 0.12 L/kg. About 32% of busulfan binds irreversibly to plasma proteins, primarily albumin, while around 7% shows reversible binding.
Metabolism: Extensive hepatic metabolism occurs predominantly through conjugation with glutathione. This process, facilitated by glutathione-S-transferase, forms a glutathione conjugate, further metabolized via oxidation.
Excretion: Busulfan is eliminated primarily through urine, with approximately 25-60% excreted as metabolites and less than 2% as an unchanged drug. Its elimination half-life is roughly 2-3 hours.
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Published on: 5 Jan 2024 12:08 PM GMT
