Busulfan – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

Busulfan is an alkylating agent that contains 2 labile methanesulfonate groups attached to opposite ends of a 4-carbon alkyl chain. Once busulfan is hydrolyzed, the methanesulfonate groups are released and carbonium ions are produced. These carbonium ions alkylate DNA, which results in the interference of DNA replication and RNA transcription, ultimately leading to the disruption of nucleic acid function. Specifically, its mechanism of action through alkylation produces guanineadenine intrastrand crosslinks. These crosslinks occur through an SN2 reaction guanine N7 nucleophilically attacks the carbon adjacent to the mesylate-leaving group. This kind of damage cannot be repaired by cellular machinery and thus the cell undergoes apoptosis.

or

The primary molecular action of busulfan is the alkylation of intracellular nucleophiles. Both proteins and nucleic acids are affected. With regard to DNA, busulfan reacts with guanine residues to form a four-carbon di-guanine DNA cross-linkage with the release of methyl sulfonate. The DNA cross-linkage causes misreading of the DNA code and single-strand breakage. The degree of DNA cross-linkage has been shown to be proportional to the dose and cytotoxicity of the compound. Busulfan-induced cross-linkages of DNA to nuclear proteins may also occur and are considered a cytotoxic mechanism. Busulfan has also been reported to esterify phosphate groups of chromosomal DNA, accounting for the fragmentation of chromosomes seen in various cell types after treatment. Chromosomal damage further contributes to the overall cytotoxic effect.

Busulfan is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands – directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn leads to a miscoding of DNA. Alkylating agents are cell cycle-nonspecific and work by three different mechanisms, all of which achieve the same end result – disruption of DNA function and cell death. Overexpression of MGST2, a glutathione s-transferase, is thought to confer resistance to busulfan. The role of MGST2 in the metabolism of busulfan is unknown however.

Indication

  • For use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous (myeloid, myelocytic, granulocytic) leukemia (FDA has designated busulfan as an orphan drug for this use). It is also used as a component of pretransplant conditioning regimens in patients undergoing bone marrow transplantation for acute myeloid leukemia and nonmalignant diseases.
  • Busulfan is used in pediatrics and adults in combination with cyclophosphamide or fludarabine/clofarabine as a conditioning agent prior to bone marrow transplantation, especially in chronic myelogenous leukemia (CML) and other leukemias, lymphomas, and myeloproliferative disorders. Busulfan can control tumor burden but cannot prevent transformation or correct cytogenic abnormalities.
  • Busulfan Fresenius Kabi followed by cyclophosphamide (BuCy2) is indicated as conditioning treatment prior to conventional hematopoietic progenitor cell transplantation (HPCT) in adult patients when the combination is considered the best available option.
  • Busulfan Fresenius Kabi followed by cyclophosphamide (BuCy4) or melphalan (BuMel) is indicated as conditioning treatment prior to conventional hematopoietic progenitor cell transplantation in pediatric patients.
  • Busilvex followed by cyclophosphamide (BuCy2) is indicated as conditioning treatment prior to conventional hematopoietic progenitor cell transplantation (HPCT) in adult patients when the combination is considered the best available option.
  • Busilvex following fludarabine (FB) is indicated as conditioning treatment prior to hematopoietic progenitor cell transplantation (HPCT) in adult patients who are candidates for a reduced-intensity conditioning (RIC) regimen.
  • Busilvex followed by cyclophosphamide (BuCy4) or melphalan (BuMel) is indicated as conditioning treatment prior to conventional hematopoietic progenitor cell transplantation in pediatric patients.
  • Essential Thrombocythemia (ET)
  • Leukemia Chronic Myelogenous Leukemia (CML)
  • Polycythemia Vera (PV)

Use in Cancer

Busulfan is approved to treat:

  • Chronic myelogenous leukemia (CML).
    • It is used as palliative treatment. This use is approved for the Myleran brand of busulfan.
    • It is also used with other drugs to prepare patients with CML for a stem cell transplant. This use is approved for the Busulfex brand of busulfan.

Busulfan is also being studied in the treatment of other types of cancer.

Contraindication

  • a bad infection
  • low amount of magnesium in the blood
  • low amount of potassium in the blood
  • significantly decreased activity of the bone marrow
  • anemia
  • decreased blood platelets
  • low levels of a type of white blood cell called neutrophils
  • hepatic veno-occlusive disease, a type of liver disease
  • a condition where there is formation of fibrous tissue in the lung called pulmonary fibrosis
  • seizures
  • high blood sugar
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • Fanconi’s anemia

Dosage

Strengths: 2 mg; 6 mg/mL

Chronic Myelogenous Leukemia

  • Initial dose: 60 mcg/kg OR 1.8 mg/m2 orally once a day
  • The usual adult dose range for remission induction is 4 to 8 mg/day
  • The dosing presented here is the manufacturer-recommended dosing. The local protocol should be consulted.
  • Since the rate of fall of the leukocyte count is dose related, daily doses exceeding 4 mg per day should be reserved for patients with the most compelling symptoms; the greater the total daily dose, the greater is the possibility of inducing bone marrow aplasia.
  • A decrease in the leukocyte count is not usually seen during the first 10 to 15 days of therapy; the leukocyte count may increase during this period and it should not be interpreted as resistance to the drug, nor should the dose be increased. Since the leukocyte count may continue to fall for more than 1 month after discontinuing the drug, it is important that it be discontinued prior to the total leukocyte count falling into the normal range. When the total leukocyte count has declined to approximately 15,000/mcL, the drug should be withheld.
  • With a constant dose of this drug, the total leukocyte count declines exponentially; a weekly plot of the leukocyte count on semi-logarithmic graph paper aids in predicting the time when therapy should be discontinued. With the recommended dose of this drug, a normal leukocyte count is usually achieved in 12 to 20 weeks.
  • During remission, the patient should be examined at monthly intervals and therapy resumed with the induction dosage when the total leukocyte count reaches approximately 50,000/mcL.
  • When remission is shorter than 3 months, maintenance therapy of 1 to 3 mg orally daily may be advisable to keep the hematological status under control and prevent rapid relapse. For the palliative treatment of chronic myelogenous (myeloid, myelocytic, granulocytic) leukemia

Bone Marrow Transplantation

  • 0.8 mg/kg ( ideal body weight or actual body weight, whichever is lower) IV via a central venous catheter as a 2-hour infusion every 6 hours for 4 consecutive days for a total of 16 doses (Days 7, 6, 5, and 4) followed by cyclophosphamide 60 mg/kg IV as a 1-hour infusion on each of 2 days beginning no sooner than 6 hours following the sixteenth dose of busulfan (Days 3 and 2); administer hematopoietic progenitor cells on Day 0
  • The dosing presented here is the manufacturer-recommended dosing. The local protocol should be consulted.
  • For obese or severely obese patients, base dosing of this drug on adjusted ideal body weight (AIBW).
  • Premedicate with prophylactic anticonvulsant therapy (e.g., phenytoin, levetiracetam, benzodiazepines, or valproic acid) beginning 12 hours prior to high-dose therapy and continuing for 24 hours after the last dose.
  • This drug is associated with a moderate emetic potential (depending on dose and/or administration route). Antiemetics may be necessary to prevent nausea and vomiting. Antiemetics are recommended when used for transplantation.
  • Administer as IV infusion. Do not administer as an IV push or bolus.

Pediatric Dose for

Chronic Myelogenous Leukemia

  • 60 mcg/kg OR 1.8 mg/m2 orally once a day
  • The dosing presented here is the manufacturer-recommended dosing. The local protocol should be consulted.
  • Since the rate of fall of the leukocyte count is dose related, daily doses exceeding 4 mg per day should be reserved for patients with the most compelling symptoms; the greater the total daily dose, the greater is the possibility of inducing bone marrow aplasia.
  • A decrease in the leukocyte count is not usually seen during the first 10 to 15 days of therapy; the leukocyte count may increase during this period and it should not be interpreted as resistance to the drug, nor should the dose be increased. Since the leukocyte count may continue to fall for more than 1 month after discontinuing the drug, it is important that it be discontinued prior to the total leukocyte count falling into the normal range. When the total leukocyte count has declined to approximately 15,000/mcL, the drug should be withheld.
  • With a constant dose of this drug, the total leukocyte count declines exponentially; a weekly plot of the leukocyte count on semi-logarithmic graph paper aids in predicting the time when therapy should be discontinued. With the recommended dose of this drug, a normal leukocyte count is usually achieved in 12 to 20 weeks.
  • During remission, the patient should be examined at monthly intervals and therapy resumed with the induction dosage when the total leukocyte count reaches approximately 50,000/mcL.
  • When remission is shorter than 3 months, maintenance therapy of 1 to 3 mg orally daily may be advisable to keep the hematological status under control and prevent rapid relapse.

Bone Marrow Transplantation

Initial Dose:

  • Less than or equal to 12 kg: 1.1 mg/kg (based on actual body weight)
  • Greater than 12 kg: 0.8 mg/kg (based on actual body weight)
  • Doses are administered every 6 hours as 2-hour infusions over 4 days for a total of 16 doses.
  • Therapeutic drug monitoring and dose adjustment following the first dose of busulfan is recommended.
  • Consult the manufacturer’s product information or local protocol for recommended dose adjustments.

Administration advice:

  • Infusion pumps should be used to administer the diluted IV injection solution. Set the flow rate of the pump to deliver the entire dose over 2 hours.
  • Prior to and following each infusion, flush the indwelling catheter line with approximately 5 mL of 0.9% sodium chloride injection or 5% dextrose injection.
  • Rapid infusion of the injection has not been tested and is not recommended.

Storage requirements:

  • Unopened vials of this drug should be stored under refrigerated conditions between 2C to 8C (36F to 46F).
  • Vials diluted with 0.9% sodium chloride injection or 5% dextrose injection are stable at room temperature (25C) for up to 8 hours but the infusion must be completed within that time.
  • Vials diluted with 0.9% sodium chloride injection are stable at refrigerated conditions (2C to 8C) for up to 12 hours but the infusion must be completed within that time.
  • Store the tablet formulation at 25C (77F); excursions are permitted to 15C to 30C (59 to 86F).

Reconstitution/preparation techniques

  • Skin reactions may occur with accidental exposure. Use gloves when preparing this drug. If the reconstituted IV solution contacts the skin or mucosa, wash the skin or mucosa thoroughly with water.
  • Due to incompatibility, do not use any infusion components containing polycarbonate with this drug.
  • Visually inspect parenteral drug products for particulate matter and discoloration prior to administration whenever the solution and container permit. Do not use if particulate matter is seen in the vial.
  • The IV injection must be diluted prior to infusion with either 0.9% sodium chloride injection or 5% dextrose injection. The diluent quantity should be 10 times the volume of busulfan injection, so that the final concentration of busulfan is approximately 0.5 mg per mL. Consult the manufacturer product information for reconstitution details.
  • Do not put the busulfan injection into an IV bag or large-volume syringe that does not contain normal saline or D5W. Always add the busulfan injection to the diluent, not the diluent to the busulfan injection. Mix thoroughly by inverting several times.

IV compatibility:

  • The IV formulation of this drug may be reconstituted with 0.9% sodium chloride injection or 5% dextrose injection.
  • Do not infuse this drug concomitantly with another IV solution of unknown compatibility.

General:

  • This drug is cytotoxic. Follow applicable special handling and disposal procedures.

Monitoring:

  • Monitor the patient for myelosuppression.

Side Effects

The Most Common

  • nausea
  • diarrhea
  • loss of appetite or weight
  • constipation
  • sores in the mouth and throat
  • dry mouth
  • headache
  • difficulty falling asleep or staying asleep
  • feeling unusually anxious or worried
  • dizziness
  • swelling of the face, arms, hands, feet, ankles or lower legs
  • chest pain
  • joint, muscle or back pain
  • skin rash
  • itching and dry skin
  • darkened skin
  • hair loss
  • black, tarry stools
  • red urine
  • unusual tiredness or weakness
  • difficulty breathing
  • changes in vision
  • vomiting
  • stomach pain
  • seizures

More Common

  • easy bruising, unusual bleeding, purple or red spots under your skin;
  • fever, chills, tiredness, sore throat;
  • cough, trouble breathing, chest pain, wheezing;
  • coughing with bloody mucus;
  • pale skin, cold hands and feet;
  • vision problems;
  • persistent cough, congestion, or breathing problems that occur several months or years after using busulfan;
  • a seizure;
  • adrenal gland problems–nausea, vomiting, loss of appetite, weight loss and severe weakness or tired feeling;
  • signs of a heart problem–stomach pain, vomiting, sharp chest pain, trouble breathing;
  • signs of liver problems–weight gain, stomach swelling or tenderness, jaundice (yellowing of the skin or eyes); o
  • signs of an electrolyte imbalance–muscle contractions, muscle weakness, leg cramps, irregular heartbeats, fluttering in your chest, increased thirst or urination, numbness or tingling.

Rare

  • red or purple skin rash with blistering and peeling,
  • easy bruising,
  • unusual bleeding,
  • chills,
  • tiredness,
  • sore throat,
  • cough,
  • wheezing,
  • coughing with bloody mucus,
  • pale skin,
  • cold hands and feet,
  • vision problems,
  • persistent cough,
  • congestion,
  • breathing problems that occur several months or years after using the medication,
  • seizure,
  • nausea,
  • vomiting,
  • loss of appetite,
  • weight loss,
  • severe weakness,
  • tired feeling,
  • stomach pain,
  • sharp chest pain,
  • weight gain,
  • stomach swelling or tenderness,
  • yellowing of the skin or eyes (jaundice),
  • muscle contractions,
  • muscle weakness,
  • leg cramps,
  • irregular heartbeats,
  • fluttering in your chest,
  • increased thirst or urination, and
  • numbness or tingling

Drug Interaction

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Pregnancy and Lactation

Pregnancy

Busulfan can cause fetal harm when administered to a pregnant woman based on animal data. Busulfan was teratogenic in mice, rats, and rabbits following administration during organogenesis. The solvent, DMA, may also cause fetal harm when administered to a pregnant woman. In rats, DMA doses of approximately 40% of the daily dose of DMA in the busulfan dose on a mg/m2 basis given during organogenesis caused significant developmental anomalies. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

Lactation

It is not known whether Busulfan is present in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for busulfan in human and animal studies, discontinue breastfeeding during treatment with BUSULFEX.

How should this medicine be used?

Busulfan comes as a tablet to take by mouth once a day. The length of treatment depends on the types of drugs you are taking, how well your body responds to them, and the type of cancer you have. Take busulfan at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take busulfan exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor may adjust your dose of busulfan depending on your response to treatment and any side effects that you experience. Talk to your doctor about how you are feeling during your treatment. Do not stop taking busulfan without talking to your doctor.

Other uses for this medicine

Busulfan tablets are also used in combination with other drugs to destroy the bone marrow and cancer cells in preparation for a bone marrow transplant.

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?

Before taking busulfan,

  • tell your doctor and pharmacist if you are allergic to busulfan, any other medications, or any of the ingredients in busulfan tablets. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: acetaminophen (Tylenol); certain chemotherapy medications such as bendamustine (Treanda), carmustine (BiCNU, Gliadel Wafer), cyclophosphamide (Cytoxan), ifosfamide (Ifex), lomustine (CeeNU), melphalan (Alkeran), procarbazine (Mutalane), temozolomide (Temodar), thioguanine; clozapine (Clozaril, FazaClo); cyclosporine (Sandimmune, Gengraf, Neoral); itraconazole (Sporanox); medications for mental illness and nausea; phenytoin (Dilantin); or meperidine (Demerol). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with busulfan, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
  • tell your doctor if you have previously received radiation therapy or treatment with other chemotherapy medications or if you have or have ever had seizures or a head injury. Also tell your doctor if you have taken busulfan before, but your cancer did not respond to the medication.
  • you should know that busulfan may interfere with the normal menstrual cycle (period) in women, may stop sperm production in men. However, you should not assume that you cannot get pregnant or that you cannot get someone else pregnant. Women who are pregnant or breast-feeding should tell their doctors before they begin taking this drug. You should not plan to have children while receiving chemotherapy or for a while after treatments. (Talk to your doctor for further details.) Use a reliable method of birth control to prevent pregnancy. If you become pregnant while taking busulfan, call your doctor immediately. Busulfan may harm the fetus.

References

  1. https://pubchem.ncbi.nlm.nih.gov/compound/Busulfan
  2. https://www.webmd.com/drugs/2/drug-14002/busulfan-oral/details/list-contraindications
  3. https://medlineplus.gov/druginfo/meds/a682248.html
  4. https://en.wikipedia.org/wiki/Busulfan
  5. https://go.drugbank.com/drugs/DB01008
  6. https://www.drugs.com/mtm/busulfan-oral-injection.html
  7. CAMEO Chemical Reactivity Classification
  8. LICENSE
    The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.
  9. ChemIDplus Chemical Information Classification
  10. CompTox Chemicals Dashboard Chemical Lists
  11. NCI Thesaurus Tree
  12. LICENSE
    The data used in DGIdb is all open access and where possible made available as raw data dumps in the downloads section.
  13. LICENSE
    Information on the European Medicines Agency’s (EMA) website is subject to a disclaimer and copyright and limited reproduction notices.
  14. LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    NORMAN Suspect List Exchange Classification
  15. 1,4-Butanediol, dimethanesulfonate
  16. IARC Classification
  17. LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
  18. LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
  19. Antineoplastic Agents, Alkylating
  20. PubChem
  21. LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    Therapeutic category of drugs in Japan
    Anatomical Therapeutic Chemical (ATC) classification
    Drugs listed in the Japanese Pharmacopoeia
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