Busulfan is an anticancer drug that interferes with cancer cells and prevents their proliferation by cross-linking DNA.

It is used in the treatment of the following conditions:

• CML (Chronic myeloid leukemia):

  • Conditioning regimen in combination with cyclophosphamide before the allogeneic hematopoietic progenitor cell transplantation for chronic myeloid leukemia (CML).

• Off Label Use of Busulfan in Adults includes:

  • Essential thrombocythemia resistant to therapy

  • For refractory or resistant polycythemia vera.

  • As oral therapy in conditioning regimen in patients with hematopoietic stem cell transplant (HSCT).

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Busulfan Dose in Adults

Note:

Patients who are undergoing high-dose busulfan treatment should be premedicated with prophylactic anticonvulsant therapy 12 hours before the treatment and continue for 24 hours after the last busulfan dose. Antiemetics may also be advised to prevent nausea and vomiting

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Busulfan dose in the treatment of resistant Essential thrombocythemia:

• Adults older than 60 years of age:
  • 2 - 4 mg orally once a day
  • Treatment should be withheld if the platelets count drops to less than 200,000/mm³ or if WBC is less than 3,000/mm³.
  • Treatment should be resumed at a lower dose i.e. 2 mg once a day.

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Hematopoietic stem cell (HSCT) conditioning regimen:

• 0.8 mg/kg/dose intravenous every 6 hours for four days to a total of 16 doses beginning 7 days before the transplant followed by cyclophosphamide (actual body weight or ideal body weight, whichever is lower should be used).
• The manufacturer recommends adjusting the dose in obese and morbidly obese patients as [IBW + 0.25 x (actual – IBW)].

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Conditioning regimens (off-label):

Note: Myeloablative conditioning regimens include total busulfan doses of more than 8 mg/kg per course and reduced-intensity conditioning regimens include total busulfan doses of less than 8 mg/kg per course.

• Bu4/Cy regimen:

  • 0.8 mg/kg intravenous every 6 hours for 16 doses (total busulfan dose of 12.8 mg/kg over four days
  • This is followed by 2 days of cyclophosphamide, then allogeneic HSCT after one day of rest.

• Flu/Bu4 regimen:

  • 0.8 mg/kg intravenous every 6 hours for 16 doses beginning six days before allogeneic transplant (total busulfan dose 12.8 mg/kg over four days in combination with four days of fludarabine or

• Reduced-intensity conditioning regimen:

  • 0.8 mg/kg intravenous once a day for four days beginning 5 days before allogeneic transplant (total busulfan dose 3.2 mg/kg over 4 days in combination with 4 days of fludarabine).

• Flu/Bu4 (once a day) regimen:

  • 130 mg/m² intravenous over three hours once a day for four days in combination with 4 days of fludarabine ± thymoglobulin, followed by allogeneic transplant
  • Busulfan should be administered after fludarabine each day.

• Bu/Cy regimens:

  • 1 mg/kg orally every six hours for 16 doses (total busulfan dose of 16 mg/kg over four days; followed by two days of cyclophosphamide, then allogeneic HSCT two days later on day 8) or
  • 1 mg/kg orally every six hours for 16 doses (total busulfan dose of 16 mg/kg over four days followed by two days of cyclophosphamide, followed by allogeneic marrow transplant) or
  • 1 mg/kg orally every 6 hours for 16 doses beginning nine days prior to transplant (total busulfan dose of 16 mg/kg over four days followed by 4 days of cyclophosphamide, followed by allogeneic or autologous marrow transplant).

• Bu/Mel regimen:

  • 1 mg/kg orally every six hours for 16 doses beginning six days prior to transplant (total busulfan dose of 16 mg/kg over four days followed by Intravenous melphalan, followed by autologous transplant).

• Bu/Mel/TT regimen:

  • 1 mg/kg orally every six hours for 12 doses beginning eight days prior to transplant (total busulfan dose of 12 mg/kg over three days, followed by two days of Intravenous melphalan and then two days of thiotepa)

• Flu/Bu2 regimen:

  • 1 mg/kg orally every 6 hours for 8 doses beginning six days prior to transplant (total busulfan dose of 8 mg/kg over two days in combination with 6 days of fludarabine and 4 days of ATG)

• Flu/Bu4:

  • 1 mg/kg orally every six hours for 16 doses (total busulfan dose of 16 mg/kg over four days in combination with 4 days of fludarabine).

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Busulfan dose in the treatment of refractory or resistant Polycythemia vera:

• 2 - 4 mg orally once a day.
• Withhold treatment when the platelets count drops to less than 200,000/mm³ or WBC is less than 3,000/mm³.
• The treatment should be resumed at a lower dose of 2 mg once a day.

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Busulfan Dose in Children:

Note:

• Patients should be premedicated with prophylactic anticonvulsant therapy 12 hours before high-dose busulfan treatment and continuing for 24 hours after the last busulfan dose.
• Antiemetics may be advised to prevent nausea and vomiting.

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Busulfan dose in Hematopoietic stem cell transplant (HSCT) conditioning regimen:

Note:

• Dosing is based on the actual body weight, including obese individuals Initial:
• Therapeutic drug monitoring should be considered early in the regimen and doses should be adjusted accordingly.
  • 12 kg or less:
    • 1.1 mg/kg/dose intravenous every 6 hours for 16 doses over four days followed by cyclophosphamide.
  • More than 12 kgs:
    • 0.8 mg/kg/dose intravenous every 6 hours for 16 doses over four days followed by cyclophosphamide

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Reduced-intensity conditioning regimens:

• 12-dose regimen:

  • Children older than 2 years and Adolescents:
    • 0.8 mg/kg/dose intravenous every 6 hours for 12 doses starting on Day 6.
    • It is used in combination with melphalan and fludarabine for patients receiving haploidentical, peripheral blood HSCT for acute leukemia.

• 8-dose regimen:

  • Infants, Children, and Adolescents:
    • 0.8 mg/kg/dose intravenous for one dose on either day 7 (related donor) or day 10 (unrelated donor or cord recipient) before the transplant
    • This is followed by 7 additional doses of 0.8 mg/kg/dose every six hours beginning on days 3 and 2 (related donor) or days 6 and 5 (unrelated donor or cord recipient) before the transplant.
    • It is used in combination with fludarabine and anti-thymocyte globulin (rabbit).

• Once-Daily Dosing:

  • Infants less than 1 year:
    • 80 mg/m²/dose intravenous over three hours once a day for four days prior to HSCT, starting on Day 8 in combination with cyclophosphamide or fludarabine and etoposide.
  • Children more than 1 year and Adolescents:
    • 120 mg/m²/dose Intravenous over three hours once a day for 4 days prior to HSCT, starting on Day 8 in combination with cyclophosphamide or fludarabine and etoposide.

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Busulfan dose in the treatment of Acute Myeloid Leukemia:

• Adolescents older than 16 years:
  • 1 mg/kg/dose orally every 6 hours for 16 doses on days 9 to 6 in combination with cyclophosphamide.

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Busulfan Dose in the Treatment of Thalassemia Major:

• Class 1 or Class 2 (ie, low-risk for GVHD or transplant mortality):

  • Infants and Children less than 3 years:
    • 1.25 mg/kg orally every six hours for 16 doses on day 9 to day 6 prior to transplant in combination with cyclophosphamide and anti-thymocyte globulin (horse).
  • Children older than 3 years and Adolescents:
    • 1 mg/kg/dose orally every six hours for 16 doses prior to transplant on days 9 to 6 in combination with cyclophosphamide and anti-thymocyte globulin (horse).

• Class 3 (i.e, high-risk disease):

  • Children older than 10 years and Adolescents:
    • 2 mg/kg/dose orally twice daily for 4 doses on days 8 and 7 in combination with fludarabine and anti-thymocyte globulin (horse).

Pregnancy Risk Factor D

Busulfan can cause fetal harm during pregnancy. Effective contraception should be used by females and males of reproductive potential during and after busulfan therapy. Busulfan's impact on breastfeeding is unknown, and intravenous busulfan is contraindicated for breastfeeding.

Busulfan Dose in Renal Disease:

Adjustment in the dose has not been recommended by the manufacturer in patients with renal disease.

Busulfan Dose in Liver Disease:

 Adjustment in the dose has not been recommended by the manufacturer in patients with liver disease.

Common Side Effects Of Busulfan injection:

• Cardiovascular:
  • Edema
  • Tachycardia
  • Hypertension
  • Thrombosis
  • Chest pain
  • Vasodilatation
• Central nervous system:
  • Insomnia
  • Anxiety
  • Headache
  • Chills
  • Pain
  • Dizziness
  • Depression
• Dermatologic:
  • Skin rash
  • Pruritus
• Endocrine & metabolic:
  • Hypomagnesemia
  • Hyperglycemia
  • Hypokalemia
  • Hypocalcemia
• Gastrointestinal:
  • Vomiting
  • Nausea
  • Mucositis
  • Stomatitis
  • Anorexia
  • Diarrhea
  • Abdominal pain
  • Dyspepsia
  • Constipation
  • Xerostomia
  • Rectal disease
  • Gastrointestinal fullness
• Hematologic & oncologic:
  • Neutropenia
  • Bone marrow depression
  • Thrombocytopenia
  • Lymphocytopenia
  • Anemia
• Hepatic:
  • Hyperbilirubinemia
  • Increased serum ALT
  • Hepatic sinusoidal obstruction syndrome
• Hypersensitivity:
  • Hypersensitivity reaction
• Immunologic:
  • Graft versus host disease
• Local:
  • Inflammation at the injection site
• Neuromuscular & skeletal:
  • Weakness
  • Back pain
• Renal:
  • Increased serum creatinine
• Respiratory:
  • Rhinitis
  • Pulmonary disease
  • Cough
  • Dyspnea
  • Epistaxis
  • Pneumonia
• Miscellaneous:
  • Fever

Less Common Side Effects Of Busulfan Include:

• Cardiovascular:
  • Cardiac tamponade

Frequency of side effects not defined:

• Cardiovascular:
  • Atrial fibrillation
  • Cardiac arrhythmia
  • Cardiomegaly
  • Catheter site thrombosis
    • Central venous catheter
  • Complete atrioventricular block
  • ECG abnormality
  • Flushing
  • Hypotension
  • Left heart failure
  • Pericardial effusion
  • Ventricular premature contractions
• Central nervous system:
  • Agitation
  • Brain disease
  • Cerebral hemorrhage
  • Coma
  • Confusion
  • Delirium
  • Drowsiness
  • Hallucination
  • Lethargy
• Dermatologic:
  • Acne vulgaris
  • Alopecia
  • Erythema nodosum
  • Exfoliative dermatitis
  • Maculopapular rash
  • Skin discoloration
  • Vesicular eruption
  • Vesiculobullous dermatitis
• Endocrine & metabolic:
  • Hot flash
  • Hypervolemia
  • Hyponatremia
  • Hypophosphatemia
  • Weight gain
• Gastrointestinal:
  • Esophagitis
  • Hematemesis
  • Hiccups
  • Intestinal obstruction
  • Pancreatitis
  • Rectal pain
• Genitourinary:
  • Dysuria
  • Hematuria
  • Hemorrhagic
  • Cystitis
  • Oliguria
• Hematologic & oncologic:
  • Prolonged prothrombin time
• Hepatic:
  • Hepatomegaly
  • Increased serum alkaline phosphatase
  • Jaundice
• Immunologic:
  • Graft versus host disease
• Infection:
  • Infection
• Local:
  • Pain at the injection site
• Neuromuscular & skeletal:
  • Arthralgia
  • Myalgia
• Otic:
  • Ear disease
• Renal:
  • Increased blood urea nitrogen
• Respiratory:
  • Asthma
  • Atelectasis
  • Hemoptysis
  • Hyperventilation
  • Hypoxia
  • Pharyngitis
  • Pleural effusion
  • Pulmonary alveolar hemorrhage
  • Pulmonary interstitial fibrosis
  • Sinusitis

Common Side Effects Of Oral Busulfan Include:

• Central nervous system:
  • Seizure
    • despite prophylactic seizure therapy
• Dermatologic:
  • Skin hyperpigmentation

Frequency of side effects that are not defined:

• Endocrine & metabolic:
  • Amenorrhea
  • Ovarian failure
• Hematologic & oncologic:
  • Bone marrow depression
    •  Anemia
    •  Leukopenia
    • Thrombocytopenia pancytopenia
• Respiratory:
  • Pulmonary interstitial fibrosis

Contraindications to Busulfan:

• Allergy reactions to busulfan and any component of this formulation
• Neutropenia and thrombocytopenia.

Warnings and Precautions

• Suppression of bone marrow [US Boxed Warning]:

Bone marrow suppression, which can cause severe and persistently low levels of neutrophils, red blood cells, and platelets, may occur. Dose reduction or withholding may be necessary, and some patients may require a repeat bone marrow biopsy.

CBC with differential counts should be monitored during transplantation until engraftment. Neutropenia can occur within 4 days of transplantation, but recovery can be seen in 13 days with prophylactic filgrastim.

Thrombocytopenia can be diagnosed in as little as 5 to 6 days. Patients should be monitored for signs and symptoms of bleeding or infection

• Cardiovascular:

Patients with Thalassemic Disease may develop a condition called cardiac tamponade if they are treated with high doses of oral busulfan and cyclophosphamide. Children may experience abdominal pain and vomiting as warning signs before developing cardiac tamponade. It is crucial to monitor patients for symptoms of cardiac tamponade and provide prompt treatment

• Gastrointestinal toxicities:

It can cause severe nausea and vomiting. Antiemetics such as Zofran (Ondansetron) should be administered before starting therapy.

• Sinusoidal obstruction syndrome of the liver:

Busulfan therapy can increase the risk of hepatic sinusoidal obstruction syndrome (veno-occlusive disease).

This risk is higher in patients who have received high doses of busulfan therapy or have had prior radiation therapy, chemotherapy, alkylating agents, or stem cell transplantation. To detect liver damage, liver function tests should be done daily for 28 days after transplantation.

• Pulmonary Toxicity:

Long-term use of busulfan can lead to lung problems such as pulmonary fibrosis (also known as Busulfan lung) and bronchopulmonary dysplasia. Symptoms may not appear until several years after treatment and can be life-threatening.

Patients may develop a cough, shortness of breath, or fever. Pulmonary function tests may show decreased lung compliance or reduced lung capacity.

Before concluding that the patient has lung problems due to busulfan, it is important to rule out other possible causes such as leukemic pulmonary infection or opportunistic pneumonia. If busulfan causes toxic side effects, treatment should be stopped immediately

• Secondary malignancies

It is possible for chromosomal alterations to occur. This may result in acute leukemia and other types of cancers.

• Seizures:

High doses of intravenous and oral therapy of busulfan have been linked to seizures, according to reports. To prevent seizures, patients should be given anticonvulsant medication before starting the transplant regimen. Patients who have experienced seizures or head trauma should not take this medication.

• Tissue dysplasia:

Busulfan has been associated with cellular dysplasia in various organs, including the lungs as well as the adrenal glands, liver, pancreas, lymph nodes, thyroid, bone marrow, and liver. Giant hyperchromatic nuclei have been observed in these organs. It's important to note that busulfan can also interfere with routine diagnostic tests, such as cervical smear tests.

Busulfan: Drug Interactions

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

 

Risk Factor C	Monitor for Adverse effects when using the following combinations
Acetaminophen	Busulfan serum concentration may be increased
Antifungal Agents	Busulfan serum concentration may be increased. Isavuconazonium sulfate is an exception
Blinatumomab	Busulfan serum concentration may be increased
Chloramphenicol Ophthalmic	May increase the toxic/adverse effects of Myelosuppressive Agents
Clozapine	Toxic/adverse effects of CloZAPine may be exacerbated by myelosuppressive agents. Particularly, there may be an increase in the risk of neutropenia
Coccidioides immitis skin test	Coccidioides immitis Skin Test may be affected by immunosuppressants
Denosumab	Might increase the toxic/adverse effects of Immunosuppressants. In particular, there may be an increase in the risk of serious infections
Fosphenytoin	Busulfan serum concentration may be decreased
Ifosfamide	Busulfan could increase the toxic/adverse effects of Ifosfamide. The risk of hemorrhagic cystitis and other complications may be elevated
Ocrelizumab	May increase the immunosuppressive effects of Immunosuppressants
Phenytoin	Busulfan serum concentration may be decreased
Pidotimod	The therapeutic effects of Pidotimod may be diminished by immunosuppressants
Promazine	May increase the myelosuppressive effects of myelosuppressive agents
Propacetamol	Busulfan serum concentration may be increased
Siponimod	Siponimod's immunosuppressive effects may be enhanced by taking immunosuppressants
Sipuleucel - T	Therapeutic effects of Sipuleucel T may be diminished by immunosuppressants
Tertomotide	Therapeutic effects of Tertomotide may be diminished by immunosuppressants
Trastuzumab	May increase the neutropenic effects of Immunosuppressants

Risk Factor D: Need to modify the treatment:

Drug	Interaction with Immunosuppressants
Baricitinib	Avoid use with azathioprine and cyclosporine. Permissible to use with methotrexate or nonbiologic DMARDs concurrently.
Deferasirox	Discontinue for 2-3 days before starting busulfan. Monitor for elevated busulfan effects and consider reduced doses.
Echinacea	May decrease effects of immunosuppressants.
Fingolimod	Avoid use with other immunosuppressants. Monitor for additive effects, such as infections.
Leflunomide	Risk of hematologic toxicities may increase with immunosuppressants. Avoid loading dosage and monitor for bone marrow suppression.
Lenograstim	Avoid use 24 hours before and after myelosuppressive chemotherapy.
Lipegfilgrastim	Avoid simultaneous use with myelosuppressive chemotherapy. Give at least 24 hours after chemotherapy.
Metronidazole	Avoid use of busulfan due to increased toxicities. Monitor closely if used together.
Nivolumab	Therapeutic effects may be diminished by immunosuppressants.
Palifermin	Can increase the adverse effects of antineoplastic agents, particularly oral mucositis. Avoid administration within 24 hours of chemotherapy.
Roflumilast	May increase the immunosuppressive effects of other immunosuppressants.
Tofacitinib	Can be used with methotrexate and nonbiologic DMARDs. Caution with more potent immunosuppressants.
Vaccines (Inactivated)	Immunosuppressants can reduce the effectiveness of vaccines. Complete all age-appropriate vaccines at least two weeks before starting immunosuppressant therapy. Re-vaccinate as needed.

Risk Factor X: Avoid the following Drugs in combination with Busulfan:

Drug	Interaction with Immunosuppressants
BCG (Intravesical)	Therapeutic effects may be diminished by immunosuppressants. Myelosuppressive agents may reduce their effectiveness.
Cladribine	May increase the immunosuppressive effects of other immunosuppressants. May increase myelosuppressive effects of myelosuppressive drugs.
Deferiprone	The neutropenic effect may be increased by myelosuppressive agents.
Dipyrone	May increase the toxic/adverse effects of myelosuppressive agents, including the risk of pancytopenia and agranulocytosis.
Natalizumab	Toxic/adverse effects may be exacerbated by immunosuppressants, particularly concurrent infections.
Pimecrolimus (Topical)	May increase the toxic/adverse effects of immunosuppressants.
Tacrolimus (Topical)	May increase the toxic/adverse effects of immunosuppressants.
Vaccines (Live)	Immunosuppressants can increase toxic/adverse effects and decrease the therapeutic effects of live-attenuated vaccines. Live-attenuated vaccines should be avoided for at least three months following immunosuppressant use.

Monitoring Parameters:

• How can you monitor therapeutic drug concentrations:

To make sure patients receiving palliative care or undergoing hematopoietic stem cell transplantation are safe, doctors need to do blood tests regularly. These tests include checking the types and amounts of cells in the blood, as well as liver function.

Doctors also need to keep a close eye on any symptoms of sinusoidal obstruction syndrome or cardiac tamponade. When taking blood samples, it's important to do it at the right time and not during the infusion.

Also, the blood sample should be taken from a different spot than where the infusion is given. After collecting the blood, it needs to be immediately placed on ice and centrifuged at a specific temperature within an hour.

The plasma from the sample should be frozen right away at a very low temperature to preserve it for later testing. If plasma busulfan concentrations need to be determined, the frozen plasma samples must be sent on dry ice.

 

How to administer Busulfan?

Antiemetics should be administered with busulfan as it is associated with a moderate emetic potential. 

When giving busulfan through an IV, it should be infused slowly over two hours using a central venous line.

Before and after each infusion, the line should be flushed with 5 ml of Dextrose water. It's important to avoid using polycarbonate syringes, filters, and IV tubings, as busulfan is not compatible with polycarbonate.

For oral busulfan, which is used only for Hematopoietic Stem Cell Transplant, high doses may be given by placing multiple tablets into an empty gelatin capsule

Mechanism of action of Busulfan:

Busulfan, a type of chemotherapy called an alkylating agent, works by cross-linking DNA and disrupting DNA transcription. It specifically reacts with the N-7 position of guanosine. Busulfan is known to be more toxic to myeloid cells than lymphoid cells, and it has a stronger impact on myeloid cells.

Pharmacokinetics	Details
Protein binding	32% of the drug's total is plasma protein bound, while 47% is bound to red blood cells
Metabolism	Metabolized in the liver through conjugation with glutathione and subsequent oxidation
Bioavailability	68% for children under six years old, 80% for adults, and older children
Eliminating half-life	Between 2 and 3 hours depending on the route of administration
Peak plasma concentration	Five minutes after intravenous administration, one hour after oral administration
Excretion	Primarily excreted via urine

International Brands of Busulfan:

• Busilvex
• Busulf
• Busulfex
• Myleran
• Myleran-2
• Myran

Busulfan brands in Pakistan:

Busulphan [Tabs 2 Mg]
Busulf	Pharmedic (Pvt) Ltd