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Busulfan: Drug information

Busulfan: Drug information
(For additional information see "Busulfan: Patient drug information" and see "Busulfan: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Experienced physician:

Busulfan is a potent drug. Busulfan oral tablets should not be used unless a diagnosis of chronic myelogenous leukemia (CML) has been adequately established and the responsible health care provider is knowledgeable in assessing response to chemotherapy.

Bone marrow suppression:

Busulfan tablets can induce severe bone marrow hypoplasia. Reduce or discontinue the dosage of oral busulfan immediately at the first sign of any unusual depression of bone marrow function as reflected by an abnormal decrease in any of the formed elements of the blood. A bone marrow examination should be performed if the bone marrow status is uncertain.

Busulfan injection causes severe and prolonged myelosuppression at the recommended dosage. Hematopoietic progenitor cell transplantation is required to prevent potentially fatal complications of the prolonged myelosuppression.

Brand Names: US
  • Busulfex;
  • Myleran
Brand Names: Canada
  • Busulfex [DSC];
  • Myleran;
  • PMS-Busulfan
Pharmacologic Category
  • Antineoplastic Agent, Alkylating Agent
Dosing: Adult

Note: Premedicate with prophylactic antiseizure therapy (eg, phenytoin, levetiracetam, benzodiazepines, or valproic acid) beginning 12 hours prior to high-dose busulfan treatment and continuing for 24 hours after the last busulfan dose (when using as a conditioning regimen for transplant). Antiemetics may be recommended to prevent nausea and vomiting; depending on dose and/or administration route, busulfan is associated with a moderate or high emetic potential in adults. Antiemetics are recommended when used for transplantation.

Essential thrombocythemia, resistant

Essential thrombocythemia, resistant (off-label use): Adults >60 years of age: Oral: 2 to 4 mg once daily (Fabris 2009; Tefferi 2011; Tefferi 2017); withhold when platelets <200,000/mm3 or WBC <3,000/mm3, and resume with the dose reduced to 2 mg once daily (Tefferi 2017).

Hematopoietic cell transplant conditioning regimen

Hematopoietic cell transplant conditioning regimen:

IV: 0.8 mg/kg/dose (ideal or actual body weight, whichever is lower) every 6 hours for 4 days (a total of 16 doses) beginning 7 days prior to transplant (followed by cyclophosphamide).

Obesity: For patients with obesity (including severe obesity), the use of an adjusted body weight [IBW + 0.25 x (actual – IBW)] is recommended (per the Busulfex manufacturer).

Conditioning regimens; regimen specific dosing (off-label): Note: Myeloablative conditioning regimens generally include total busulfan doses >8 mg/kg (per course) and reduced intensity conditioning regimens typically include total busulfan doses ≤8 mg/kg (per course).

Bu4/Cy regimen: IV: 0.8 mg/kg every 6 hours for 16 doses (total busulfan dose of 12.8 mg/kg over 4 days; followed by 2 days of cyclophosphamide, then allogeneic HSCT after 1 day of rest) (Andersson 2002).

Flu/Bu4 regimen: IV: 0.8 mg/kg every 6 hours for 16 doses beginning 6 days before allogeneic transplant (total busulfan dose 12.8 mg/kg over 4 days; in combination with 4 days of fludarabine) (Rambaldi 2015) or (reduced intensity conditioning regimen): 0.8 mg/kg once daily for 4 days beginning 5 days before allogeneic transplant (total busulfan dose 3.2 mg/kg over 4 days; in combination with 4 days of fludarabine) (Ho 2009).

Flu/Bu4 (once daily) regimen: IV: 130 mg/m2 over 3 hours once daily for 4 days (in combination with 4 days of fludarabine ± thymoglobulin [administer busulfan after fludarabine each day], followed by allogeneic transplant) (De Lima 2004; Madden 2007).

Bu/Cy regimens: Oral: 1 mg/kg every 6 hours for 16 doses (total busulfan dose of 16 mg/kg over 4 days; followed by 2 days of cyclophosphamide, then allogeneic HSCT 2 days later on day 8) (Tutschka 1987) or 1 mg/kg every 6 hours for 16 doses (total busulfan dose of 16 mg/kg over 4 days; followed by 2 days of cyclophosphamide, followed by allogeneic marrow transplant) (Socié 2001) or 1 mg/kg every 6 hours for 16 doses beginning 9 days prior to transplant (total busulfan dose of 16 mg/kg over 4 days; followed by 4 days of cyclophosphamide, followed by allogeneic or autologous marrow transplant) (Cassileth 1993; Cassileth 1998).

Bu/Mel regimen: Oral: 1 mg/kg every 6 hours for 16 doses beginning 6 days prior to transplant (total busulfan dose of 16 mg/kg over 4 days; followed by IV melphalan, followed by autologous transplant) (Fermand 2005).

Bu/Mel/TT regimen: Oral: 1 mg/kg every 6 hours for 12 doses beginning 8 days prior to transplant (total busulfan dose of 12 mg/kg over 3 days; followed by 2 days of IV melphalan and then 2 days of thiotepa (Schiffman 1997).

Flu/Bu2 regimen: Oral: 1 mg/kg every 6 hours for 8 doses beginning 6 days prior to transplant (total busulfan dose of 8 mg/kg over 2 days; in combination with 6 days of fludarabine and 4 days of ATG) (Slavin 1998).

Flu/Bu4: Oral: 1 mg/kg every 6 hours for 16 doses (total busulfan dose of 16 mg/kg over 4 days; in combination with 4 days of fludarabine) (Scott 2017).

Myeloablative conditioning prior to betibeglogene autotemcel in beta thalassemia

Myelo ablative conditioning prior to betibeglogene autotemcel in beta thalassemia (off-label use): IV: 3.2 mg/kg/day over 3 hours for 4 consecutive days on day −6 to day −3 or 0.8 mg/kg over 2 hours every 6 hours for 4 consecutive days (on day −6 to day −3) for a total of 16 doses; adjust busulfan dose based on busulfan pharmacokinetics (Locatelli 2022). Allow at least 48 hours to elapse after the last busulfan dose prior to administering betibeglogene autotemcel. Refer to protocol for further details.

Polycythemia vera, refractory/resistant

Polycythemia vera, refractory/resistant (off-label use): Oral: Initial: 2 to 4 mg once daily (BSH [McMullin 2018]; Tefferi 2017; Vannucchi 2014). Withhold when platelets <200,000/mm3 or WBC <3,000/mm3, and resume with the dose reduced to 2 mg once daily (Tefferi 2017). Lower maintenance doses may be used in some patients (Vannucchi 2014).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

IV: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Oral: There are no dosage adjustments provided in the manufacturer's labeling (elimination appears to be independent of renal function); however, it has been suggested that adjustment is not necessary (Aronoff 2007).

Dosing: Hepatic Impairment: Adult

IV: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Oral: There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Pediatric

(For additional information see "Busulfan: Pediatric drug information")

Note: Dose, frequency, number of doses, and/or start date may vary by protocol and treatment phase. Refer to individual protocols and/or therapeutic drug monitoring. Premedicate with prophylactic antiseizure therapy (eg, phenytoin, levetiracetam, benzodiazepines, valproic acid) beginning 12 hours prior to high-dose busulfan treatment and continuing for 24 hours after last busulfan dose. The units of measure for the busulfan AUC (ie, busulfan plasma exposure units) have been modified; previously micromolar/minute was used; however, newer consensus recommends mg × hour/L or mg(hour)/L; use caution when interpreting AUC (McCune 2019).

Busulfan is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (POGO [Paw Cho Sing 2019]). Antiemetics are recommended when used for transplantation.

Hematopoietic stem cell transplant conditioning regimen

Hematopoietic stem cell transplant (HSCT) conditioning regimen:

IV: Infants, Children, and Adolescents:

Every-6-hour dosing: Note: Although busulfan dosed every 6 hours has been frequently reported in various HSCT conditioning regimens, more recent protocols and expert consensus have suggested that every-24-hours dosing be used; see "Every-24-Hours Dosing" for suggested dosing conversion; refer to specific protocol for appropriate dose interval (ASBMT [Palmer 2016]). Therapeutic drug monitoring should be considered early in regimen (eg, after first dose) and doses adjusted accordingly. Dosing is based on actual body weight or adjusted body weight in overweight individuals (Zao 2015); refer to individual protocols.

Initial:

≤12 kg: IV: 1.1 mg/kg/dose every 6 hours for 16 doses (over 4 days followed by cyclophosphamide).

>12 kg: IV: 0.8 mg/kg/dose every 6 hours for 16 doses (over 4 days followed by cyclophosphamide).

Dosing adjustment: Doses are adjusted based upon AUC. The desired AUCs are variable and may be dependent upon multiple factors, including indication for transplant, type of transplant, and donor source; specific protocols should be consulted. A desired AUC of ~3.6 to 6.2 mg × hour/L (ASBMT [Palmer 2016]; McCune 2019) or 900 to 1,350 micromolar/minute (manufacturer's labeling) has been suggested. Adjusted dose may be determined from the following formula:

Adjusted dose (mg) = Actual dose (mg) × [target AUC (mg × hour/L) / actual AUC (mg × hour/L)]

Every-24-hours dosing: Limited data available:

Initial: To increase likelihood of target busulfan exposure being achieved early in therapy, utilization of a larger dose every 24 hours has been suggested to replace every-6-hours dosing in some protocols; refer to specific protocols for busulfan dose and frequency. The initial dose is based off of European Medicines Agency (EMA) every-6-hour dosing and a once-daily dose is then calculated. Dose calculations should be based on actual body weight and therapeutic drug monitoring should be considered early in regimen (eg, after first dose) and doses adjusted accordingly (ASBMT [Palmer 2016]; Busilvex European Medicines Agency 2021):

Busulfan Every-24-Hours Dosing

Weight (kg)

EMA Every-6-Hours Busulfan Dose (mg/kg)a

Every-24-Hours Busulfan Dose (mg/kg)

a Dosing for every 6 hours was used to calculate every-24-hours dosing.

<9 kg

1 mg/kg

4 mg/kg

9 to <16 kg

1.2 mg/kg

4.8 mg/kg

16 to <23 kg

1.1 mg/kg

4.4 mg/kg

23 to 34 kg

0.95 mg/kg

3.8 mg/kg

>34 kg

0.8 mg/kg

3.2 mg/kg

Dosing adjustment: Doses are adjusted based upon AUC. The desired AUCs are 15.6 to 24.6 mg × hour/L or 3,800 to 6,000 micromolar/minute (ASBMT [Palmer 2016]). Adjusted dose may be determined from the following formula:

Adjusted dose (mg) = Actual dose (mg) × [target AUC (mg × hour/L) / actual AUC (mg × hour/L)]

Reduced intensity conditioning regimens: Limited data available:

12-dose regimen: Children ≥2 years and Adolescents: IV: 0.8 mg/kg/dose every 6 hours for 12 doses starting on day −6; used in combination with fludarabine and melphalan for patients receiving haploidentical, peripheral blood HSCT for acute leukemia (Jaiswal 2016).

8-dose regimen: Infants, Children, and Adolescents: 0.8 mg/kg/dose for one dose on either day −7 (related donor) or day −10 (unrelated donor or cord recipient) prior to transplant, followed by 7 additional doses of ~0.8 mg/kg/dose every 6 hours (actual dose based on pharmacokinetic analysis after initial dose) beginning days −3 and −2 (related donor) or days −6 and −5 (unrelated donor or cord recipient) prior to transplant; used in combination with fludarabine and antithymocyte globulin (rabbit). In clinical trials, there was no minimum age for inclusion; the youngest patient treated was 2 years (Pulsipher 2009).

Oral:

Note: Not routinely used for HSCT conditioning regimens; IV formulation is the preferred dosage form. Dosing is variable and dependent upon indication for HSCT. For busulfan IV dosing, use of an adjusted body weight is suggested (Zao 2015); however, for oral dosing, pediatric-specific data are lacking and based on adult data; dosing based on actual body weight is suggested in overweight individuals (Bubalo 2014).

Acute myeloid leukemia: Limited data available: Adolescents ≥16 years: Oral: 1 mg/kg/dose every 6 hours for 16 doses on days −9 to −6 in combination with cyclophosphamide (Cassileth 1998).

Thalassemia major: Limited data available:

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

Infants and Children <3 years: Oral: 1.25 mg/kg every 6 hours for 16 doses on day −9 to day −6 prior to transplant in combination with cyclophosphamide and antithymocyte globulin (horse) (Hussein 2013).

Children ≥3 years and Adolescents: Oral: 1 mg/kg/dose every 6 hours for 16 doses on day −9 to day −6 prior to transplant in combination with cyclophosphamide and antithymocyte globulin (horse) (Hussein 2013).

Class 3 (ie, high-risk disease): Children ≥10 years and Adolescents: Oral: 2 mg/kg/dose every 12 hours for 4 doses on days −8 and −7 in combination with fludarabine and antithymocyte globulin (horse) (Hussein 2013).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

IV: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Oral: There are no dosage adjustments provided in the manufacturer's labeling; elimination appears to be independent of renal function; some clinicians suggest adjustment is not necessary (Aronoff 2007).

Dosing: Hepatic Impairment: Pediatric

IV: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Oral: There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Older Adult

Oral: Refer to adult dosing. Start with lowest recommended doses for adults.

Dosing: Obesity: Adult

Busulfan (IV): For patients with obesity (including severe obesity), use of an adjusted body weight [IBW + 0.25 × (actual – IBW)] is recommended (per the Busulfex manufacturer).

American Society for Blood and Marrow Transplantation (ASBMT) practice guideline committee position statement on chemotherapy dosing in obesity (ASBMT [Bubalo 2014]):

Busulfan (oral): Note: For total doses over 12 mg/kg (per cycle), utilize pharmacokinetically targeted dosage (as appropriate for disease state). When busulfan and cyclophosphamide are used in combination for hematopoietic cell transplantation conditioning, the maximum tolerated busulfan dose is 4 mg/kg/day for 4 days. The maximum tolerated busulfan dose has not been determined when used in combination with other agents.

Body surface area (BSA) dosing: Adults: Utilize actual body weight (ABW) to calculate BSA

Weight based dosing (mg/kg): Adults: Utilize ABW25 for patients with or without obesity

ABW25: Adjusted wt (kg) = Ideal body weight (kg) + 0.25 [actual wt (kg) - ideal body weight (kg)]

Dosing: Adjustment for Toxicity: Adult

Cardiac tamponade: Promptly evaluate and treat if cardiac tamponade is suspected.

Hematologic toxicity: May require platelet or RBC transfusion support and/or antibiotics.

Pulmonary toxicity: Discontinue busulfan.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Generic: 6 mg/mL (10 mL)

Solution, Intravenous [preservative free]:

Busulfex: 6 mg/mL (10 mL) [contains polyethylene glycol (macrogol)]

Generic: 6 mg/mL (10 mL)

Tablet, Oral:

Myleran: 2 mg

Generic Equivalent Available: US

May be product dependent

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous:

Busulfex: 6 mg/mL ([DSC]) [contains polyethylene glycol (macrogol)]

Generic: 6 mg/mL (10 mL)

Tablet, Oral:

Myleran: 2 mg

Administration: Adult

Antiemetics may be recommended to prevent nausea and vomiting; depending on dose and/or administration route, busulfan is associated with a moderate or high emetic potential in adults. Antiemetics are recommended when used for transplantation.

IV: Intravenous busulfan should be infused over 2 hours via central line. Once daily IV busulfan (off-label dose) has been infused over 3 hours (De Lima 2004; Locatelli 2022; Madden 2007). Use an administration set with a minimal residual priming volume (2 to 5 mL). Flush line before and after each infusion with 5 mL D5W or NS. Busulfan IV is incompatible with polycarbonate; do not use syringes, filters, or IV tubing containing polycarbonate for preparation or administration.

Busulfan injection contains N,N-dimethylacetamide, which may be incompatible with some closed-system transfer devices (CSTDs); the plastic components of some CSTDs may dissolve and result in subsequent leakage and potential infusion of dissolved plastic into the patient (ISMP [Smetzer 2015]). Refer to the specific CSTD device manufacturer for compatibility data.

Oral (HSCT only): To facilitate ingestion of high oral doses, may place multiple tablets into an empty gelatin capsule.

Administration: Pediatric

Busulfan is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (POGO [Paw Cho Sing 2019]). Antiemetics are recommended when used for transplantation.

Oral: May be administered without regard to meals. To facilitate ingestion of high doses (for hematopoietic stem cell transplant [HSCT]), may insert multiple tablets into clear gelatin capsules for administration.

Parenteral: Infusion time is dependent on dosing interval; for every-6-hours dosing, infuse over 2 hours; in trials for every-24-hours administration, doses were infused over 3 hours (Ryu 2007) or as defined in specific protocols or institutional policy. Administer through a central venous catheter; use an administration set with a minimal residual priming volume (1 to 3 mL for pediatric patients); flush line before and after each infusion with 5 mL of D5W or NS. Do not use polycarbonate syringes, filter needles, or IV tubing for preparation or administration.

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 1]).

Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).

Use: Labeled Indications

Chronic myeloid leukemia: Injection: Conditioning regimen (in combination with cyclophosphamide) prior to allogeneic hematopoietic progenitor cell transplantation for chronic myeloid leukemia (CML)

Use: Off-Label: Adult

Essential thrombocythemia, resistant; Hematopoietic cell transplant (oral), conditioning regimen; Myeloablative conditioning prior to betibeglogene autotemcel in beta thalassemia; Polycythemia vera, refractory/resistant

Medication Safety Issues
Sound-alike/look-alike issues:

Myleran may be confused with Alkeran, Leukeran, melphalan, Mylicon

High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Other safety concerns:

A solvent in IV busulfan, N,N-dimethylacetamide, may be incompatible with some closed system transfer devices (CSTDs) used for preparing injectable antineoplastics. The plastic components of some CSTDs may dissolve and result in subsequent leakage and potential infusion of dissolved plastic into the patient (ISMP [Smetzer 2015]). Refer to the specific CSTD device manufacturer for compatibility data.

Busulfan IV is incompatible with polycarbonate; do not use syringes, filters, or IV tubing containing polycarbonate.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

Intravenous:

>10%:

Cardiovascular: Edema (28% to 36%), tachycardia (44%), hypertension (36%), thrombosis (33%), chest pain (26%), vasodilation (25%)

Central nervous system: Insomnia (84%), anxiety (72%), headache (69%), chills (46%), pain (44%), dizziness (30%), depression (23%)

Dermatologic: Skin rash (57%), pruritus (28%)

Endocrine & metabolic: Hypomagnesemia (77%), hyperglycemia (66%), hypokalemia (64%), hypocalcemia (49%)

Gastrointestinal: Vomiting (95% to 100%), nausea (adults 98%; children 83%), mucositis (≤97%), stomatitis (adults ≤97%; children 79%), anorexia (85%), diarrhea (84%; grades 3/4: 5%), abdominal pain (72%), dyspepsia (44%), constipation (38%), xerostomia (26%), rectal disease (25%), gastrointestinal fullness (23%)

Hematologic & oncologic: Neutropenia (100%; onset: 4 days; median recovery: 13 days [with G-CSF support]), bone marrow depression (≤100%), thrombocytopenia (98%; median onset: 5 to 6 days), lymphocytopenia (children: 79%), anemia (69%)

Hepatic: Hyperbilirubinemia (49%), increased serum ALT (31%), hepatic sinusoidal obstruction syndrome (formerly known as hepatic veno-occlusive disease; children: 21%; adults: 8% to 12%)

Hypersensitivity: Hypersensitivity reaction (26%)

Immunologic: Graft versus host disease (children: 25%)

Local: Inflammation at injection site (25%)

Neuromuscular & skeletal: Weakness (51%), back pain (23%)

Renal: Increased serum creatinine (21%)

Respiratory: Rhinitis (44%), pulmonary disease (34%), cough (28%), dyspnea (25%), epistaxis (25%), pneumonia (children: 21%)

Miscellaneous: Fever (80%)

1% to 10%: Cardiovascular: Cardiac tamponade (children with thalassemia: 2%)

Frequency 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 (adults)

Infection: Infection

Local: Pain at 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

Oral:

1% to 10%:

Central nervous system: Seizure (2%; despite prophylactic seizure therapy)

Dermatologic: Skin hyperpigmentation (5% to 10%)

Frequency not defined:

Endocrine & metabolic: Amenorrhea, ovarian failure

Hematologic & oncologic: Bone marrow depression (including anemia, leukopenia, thrombocytopenia), pancytopenia

Respiratory: Pulmonary interstitial fibrosis

IV and/or Oral: <1%, postmarketing, and/or case reports: Acute leukemia, adrenocortical insufficiency, alopecia (permanent), anhidrosis, aplastic anemia (may be irreversible), azoospermia, capillary leak syndrome, cardiomyopathy (endocardial fibrosis), cataract (rare), cheilosis, cholestatic jaundice, corneal thinning, dry mucous membranes, enamel hypoplasia, erythema multiforme, esophageal varices (with continuous busulfan and thioguanine therapy), febrile neutropenia, fragile skin, gynecomastia, hepatic fibrosis (centrilobular sinus), hepatic necrosis, hepatic sinusoidal obstruction syndrome (formerly known as hepatic veno-occlusive disease) (oral), lens disease (including particulate matter deposition), malignant neoplasm, myasthenia gravis, porphyria cutanea tarda, pulmonary fibrosis (with bronchopulmonary dysplasia), recall skin sensitization (skin rash), sepsis, sterility, testicular atrophy, thrombotic thrombocytopenic purpura, tumor lysis syndrome, urticaria, xeroderma

Contraindications

Hypersensitivity to busulfan or any component of the formulation; oral busulfan is contraindicated in patients without a definitive diagnosis of chronic myeloid leukemia

Canadian labeling: Additional contraindications (not in the US labeling): Oral busulfan: Neutropenia or thrombocytopenia; disease that has demonstrated resistance to busulfan

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Severe and prolonged bone marrow suppression commonly occurs; reduce dose or discontinue oral busulfan for unusual suppression; may require bone marrow biopsy. Hematopoietic progenitor cell transplantation is required to prevent potentially fatal complications from prolonged myelosuppression due to IV busulfan. May result in severe neutropenia, thrombocytopenia, anemia, bone marrow failure, and/or severe pancytopenia; pancytopenia may be prolonged (1 month up to 2 years) and may be reversible. The onset of neutropenia is a median of 4 days post-transplant; recovery is within a median of 13 days following allogeneic transplant (with prophylactic filgrastim use in most patients). Thrombocytopenia occurred at a median of 5 to 6 days. Use with caution in patients with compromised bone marrow reserve (due to prior treatment or radiation therapy).

• Cardiovascular: Cardiac tamponade has been reported in children with thalassemia treated with high dose oral busulfan in combination with cyclophosphamide. Abdominal pain and vomiting preceded tamponade in most children.

• Hepatic sinusoidal obstruction syndrome: High busulfan area under the concentration versus time curve (AUC) values (>1,500 micromolar•minute) with every-6-hours dosing are associated with increased risk of hepatic sinusoidal obstruction syndrome (SOS; formerly called veno-occlusive disease [VOD]) due to conditioning for allogenic hematopoietic cell transplant. Patients with a history of radiation therapy, prior chemotherapy (≥3 cycles), or prior hematopoietic cell transplantation are also at increased risk of hepatic SOS at recommended dosing regimens. Oral busulfan doses above 16 mg/kg (based on IBW) and concurrent use with alkylating agents may also increase the risk for hepatic SOS.

• Pulmonary toxicity: Bronchopulmonary dysplasia with pulmonary fibrosis (“busulfan lung”) is associated with chronic busulfan use; onset is delayed with symptoms occurring at an average of 4 years (range: 4 months to 10 years) after treatment; may be fatal. Symptoms generally include a slow onset of cough, dyspnea and fever (low-grade), although acute symptomatic onset may also occur. Diminished diffusion capacity and decreased pulmonary compliance have been noted with pulmonary function testing. Differential diagnosis should rule out opportunistic pulmonary infection or leukemic pulmonary infiltrates; may require lung biopsy. Pulmonary toxicity may be additive if administered with other cytotoxic agents also associated with pulmonary toxicity.

• Secondary malignancies: Tumors and acute leukemias have been reported following use. Chromosomal alterations may also occur.

• Seizures: Seizures have been reported with IV busulfan and with high-dose oral busulfan. When using as a conditioning regimen for transplant, initiate prophylactic antiseizure therapy (eg, phenytoin, levetiracetam, benzodiazepines, or valproic acid) prior to treatment. Use with caution in patients predisposed to seizures, with a history of seizures, head trauma, or with other medications associated with inducing seizures.

• Tissue dysplasia: Cellular dysplasia in many organs has been observed (in addition to lung dysplasia); giant hyperchromatic nuclei have been noted in adrenal glands, liver, lymph nodes, pancreas, thyroid, and bone marrow. May obscure routine diagnostic cytologic exams (eg, cervical smear).

Concurrent drug therapy issues:

• Antiseizure medications: Phenytoin increases busulfan clearance by ≥15%; busulfan kinetics and dosing recommendations for high-dose hematopoietic cell transplant conditioning were studied with concomitant phenytoin. If alternate antiseizure medications are used, busulfan clearance may be decreased and dosing should be monitored accordingly.

Dosage form specific issues:

• Busulfan injection: The solvent in IV busulfan, dimethylacetamide (DMA) may be associated with hepatotoxicity, hallucinations, somnolence, lethargy, and confusion.

Metabolism/Transport Effects

None known.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Acetaminophen: May increase the serum concentration of Busulfan. Risk C: Monitor therapy

Androgens: Hypertension-Associated Agents may enhance the hypertensive effect of Androgens. Risk C: Monitor therapy

Baricitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination

BCG Products: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination

Blinatumomab: May increase the serum concentration of Busulfan. Risk C: Monitor therapy

Brincidofovir: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination

Cladribine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing cytotoxic chemotherapy several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification

COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters). Risk D: Consider therapy modification

COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy

COVID-19 Vaccine (mRNA): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modification

COVID-19 Vaccine (Subunit): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy

COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy

Deferasirox: May increase the serum concentration of Busulfan. Management: Discontinue deferasirox 2 to 3 days (approximately 5 half-lives) before initiation of busulfan. If combined, monitor for increased busulfan concentrations and effects. Decreased busulfan doses may be required during concomitant use. Risk D: Consider therapy modification

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification

Dengue Tetravalent Vaccine (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination

Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and cytotoxic chemotherapy. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification

Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination

Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination

Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Fosphenytoin: May decrease the serum concentration of Busulfan. Risk C: Monitor therapy

Ifosfamide: Busulfan may enhance the adverse/toxic effect of Ifosfamide. Specifically, the risk of hemorrhagic cystitis may be increased. Risk C: Monitor therapy

Inebilizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy

Influenza Virus Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating chemotherapy if possible. If vaccination occurs less than 2 weeks prior to or during chemotherapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification

Itraconazole: May increase the serum concentration of Busulfan. Risk C: Monitor therapy

Leflunomide: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents, such as cytotoxic chemotherapy. Risk D: Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification

MetroNIDAZOLE (Systemic): May increase the serum concentration of Busulfan. Management: The toxic effects of busulfan may be greatly increased with concomitant use of metronidazole. This combination should probably be avoided when possible. If these agents must be used together, increased monitoring for busulfan toxicity is recommended. Risk D: Consider therapy modification

Natalizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination

Ocrelizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy

Ofatumumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy

Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Risk D: Consider therapy modification

Phenytoin: May decrease the serum concentration of Busulfan. Risk C: Monitor therapy

Pidotimod: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy

Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Pneumococcal Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy

Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination

Polymethylmethacrylate: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Propacetamol: May increase the serum concentration of Busulfan. Risk C: Monitor therapy

Rabies Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification

Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification

Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination

Ruxolitinib (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination

Sipuleucel-T: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants, such as cytotoxic chemotherapy, prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification

Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Risk C: Monitor therapy

Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk C: Monitor therapy

Tacrolimus (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination

Talimogene Laherparepvec: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination

Tertomotide: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination

Tofacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination

Typhoid Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination

Upadacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination

Vaccines (Inactivated/Non-Replicating): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of chemotherapy when possible. Patients vaccinated less than 14 days before initiating or during chemotherapy should be revaccinated at least 3 months after therapy is complete. Risk D: Consider therapy modification

Vaccines (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Yellow Fever Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination

Reproductive Considerations

Patients who could become pregnant should use effective contraception to avoid pregnancy during treatment and for 6 months after completion of therapy. Patients with partners who could become pregnant should use effective contraception during treatment and for 3 months after completion of therapy.

Busulfan may impair fertility in females and males. Busulfan has been associated with ovarian suppression and amenorrhea. High-dose busulfan may cause temporary or permanent infertility in prepubertal females or in females of childbearing potential. Sterility, azoospermia, and testicular atrophy may occur in males.

Pregnancy Considerations

Based on animal reproduction studies, busulfan may cause fetal harm if administered during pregnancy. The solvent in IV busulfan, DMA, is also associated with teratogenic effects in animal studies.

Breastfeeding Considerations

It is not known if busulfan is present in breast milk.

According to the manufacturer, the decision to discontinue breastfeeding during therapy or to discontinue busulfan should take into account the benefits of treatment to the mother; breastfeeding should be discontinued during IV busulfan treatment.

Monitoring Parameters

CBC with differential and platelet count (weekly for palliative treatment; daily during treatment and until engraftment for hematopoietic cell transplant [HCT]); liver function tests (evaluate transaminases, alkaline phosphatase, and bilirubin daily for at least 28 days post transplant). Monitor for signs/symptoms of cardiac tamponade, sinusoidal obstruction syndrome, infection, and bleeding.

The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

If conducting therapeutic drug monitoring for AUC calculations in HCT, monitor blood samples at appropriate collections times (record collection times). Do not collect blood sample during busulfan infusion; collect blood sample from a different port than that used for infusion. Blood samples should be placed on wet ice immediately after collection and should be centrifuged (at 4°C [39.2°F]) within 1 hour. The plasma, harvested into appropriate cryovial storage tubes, should be frozen immediately at −20°C (−4°F). All plasma samples should be sent frozen (on dry ice) to the assay laboratory for the determination of plasma busulfan concentrations.

Mechanism of Action

Busulfan is an alkylating agent which reacts with the N-7 position of guanosine and interferes with DNA replication and transcription of RNA. Busulfan has a more marked effect on myeloid cells than on lymphoid cells and is also very toxic to hematopoietic cells. Busulfan exhibits little immunosuppressive activity. It interferes with the normal function of DNA by alkylation and cross-linking the strands of DNA.

Pharmacokinetics

Absorption: Rapid and complete

Distribution: Vd: Pediatric (IV): ~0.64 L/kg; crosses blood brain barrier and distributes into CSF with levels equal to plasma

Protein binding: ~32% to plasma proteins and 47% to red blood cells

Metabolism: Extensively hepatic (may increase with multiple doses); glutathione conjugation followed by oxidation

Bioavailability: Oral: Children ≥13 years and adults: 80% (range: 47% to 103%); Children 1.5 to 6 years: 68% (range: 22% to 120%)

Half-life elimination: 2 to 3 hours

Time to peak, serum: Oral: ~1 hour; IV: Within 5 minutes

Excretion: Urine (25% to 60% predominantly as metabolites; <2% as unchanged drug)

Clearance: Children: 3.37 mL/minute/kg; Adults: 2.52 mL/minute/kg (range: 1.49 to 4.31 mL/minute/kg)

Pharmacokinetics: Additional Considerations

Altered kidney function: In a patient with chronic renal failure undergoing autologous hematopoietic cell transplantation, the apparent oral clearance of busulfan during a 4-hour hemodialysis session was increased 65%, but the 24-hour oral clearance of busulfan was increased only 11%.

Pricing: US

Solution (Busulfan Intravenous)

6 mg/mL (per mL): $13.80 - $248.40

Solution (Busulfex Intravenous)

6 mg/mL (per mL): $60.00

Tablets (Myleran Oral)

2 mg (per each): $150.00

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Bucelon (IN);
  • Busilvex (AT, BE, BG, CH, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HN, HR, IE, IT, LB, MT, NL, NO, PL, PT, RO, RU, SE, SK, TR);
  • Busulf (PK);
  • Busulfex (AU, CN, HK, IL, JP, KR, MY, SG, TH, TW, VN);
  • Myleran (AE, AR, AT, AU, BB, BE, BF, BG, BH, BJ, BM, BR, BS, BZ, CH, CI, CL, CR, CY, CZ, DE, DO, EC, EE, EG, ET, FR, GB, GH, GM, GN, GT, GY, HN, HR, IE, IL, IN, IQ, IR, IS, IT, JM, JO, KE, KW, LB, LK, LR, LT, LU, LY, MA, ML, MR, MT, MU, MW, MX, MY, NE, NG, NI, NL, NZ, OM, PA, PE, PL, PT, QA, RO, RU, SA, SC, SD, SE, SG, SI, SK, SL, SN, SR, SV, SY, TH, TN, TR, TT, TW, TZ, UG, UY, YE, ZA, ZM, ZW);
  • Myleran-2 (CU);
  • Myran (IN)


For country code abbreviations (show table)
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