Busulfan

Trade Names:Busulfex- Solution for injection 6 mg/mL

Trade Names:Myleran- Tablets 2 mg

Pharmacology

Predominantly effective against cells of the granulocytic series. Although a polyfunctional alkylating agent, it appears to interact with cellular thiol groups. The drug is cell cycle-phase nonspecific; however, alkylation of the DNA is considered an important biological mechanism for its cytotoxic effect.

Pharmacokinetics

Absorption

C _max is about 1,222 ng/mL.

Well absorbed.

Distribution

Concentrations in CSF are approximately equivalent to those in plasma. Busulfan is approximately 32.4% protein bound, primarily to albumin.

Metabolism

Metabolized predominantly by conjugation with glutathione. This conjugate is further oxidized in the liver.

Elimination

About 30% excreted in urine over 48 h; negligible amounts are excreted in the feces; t _½ is 2.5 h.

Cl is about 2.52 mL/min/kg.

Indications and Usage

Palliative treatment of chronic myelogenous leukemia (CML) (oral); in combination with cyclophosphamide as a conditioning regimen prior to allogeneic bone marrow transplantation for CML (IV).

Unlabeled Uses

Severe thrombocytosis, polycythemia vera, myelofibrosis, bone marrow transplantation (oral).

Contraindications

Do not use unless a diagnosis of CML has been adequately established (oral); hypersensitivity to any of its components (IV, oral).

Dosage and Administration

PO 4 to 8 mg/day (60 mcg/kg or 1.8 mg/m ² /day). Withhold drug when the total leukocyte count is less than 15,000/mm ³ . During remission, treatment is resumed when a monthly WBC reaches 50,000/mm ³ .

PO 60 mcg/kg or 1.8 mg/m ² once daily. Withhold drug when total leukocyte count is less than 15,000/mm ³ . During remission, treatment is resumed when a monthly WBC reaches 50,000/mm ³ .

IV 0.8 mg/kg every 6 h for 16 doses (for a total dose of 12.8 mg/kg over 4 days). Base dose on ideal body weight or actual body weight, whichever is lower. For obese patients, base dosage on adjusted body weight.

General Advice

• Injection
• Withdraw dose from the ampule using the provided 5 micron filter needle. Remove the filter needle and use a new needle to add busulfan to the diluent.
• Dilute solution for injection with dextrose 5% or sodium chloride 0.9% , for a final busulfan concentration of about 0.5 mg/mL. Add the busulfan to the diluent; do not add the diluent to busulfan.
• Diluted busulfan solutions are stable for up to 8 h at room temperature (59° to 86°F) and for up to 12 h under refrigeration, but infusion must be completed within that time.
• Follow safe handling procedures and disposal of chemotherapy drugs. Wear gloves; avoid skin contact and inhalation of fumes.
• Infuse over 2 h. Vigorous hydration reduces the risk of renal toxicity.
• Visually inspect for particulate matter and discoloration prior to administration; do not use if particulate matter is seen.

Storage/Stability

Store tablets at 59° to 86°F. Store unopened injection ampules in refrigerator (36° to 46°F).

Drug Interactions

May decrease busulfan Cl.

Decreases busulfan Cl 25%, increasing serum levels and effects.

Busulfan trough levels may be elevated about 80%, increasing the risk of serious toxicity.

Increases busulfan Cl at least 15%, reducing serum levels and effects.

Long-term, concomitant use has resulted in hepatotoxicity and esophageal varices.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Cardiac tamponade.

Tachycardia (44%); hypertension (36%); thrombosis (33%); vasodilation (25%); hypotension (11%); arrhythmia, cardiomegaly (5%); atrial fibrillation, left-sided heart failure, mild ECG abnormality, pericardial effusion, third-degree heart block, ventricular extrasystoles (2%).

CNS

Seizures.

Insomnia (84%); anxiety (72%); headache (69%); asthenia (51%); dizziness (30%); depression (23%); confusion (11%); lethargy (7%); hallucinations (5%); agitation, delirium, encephalopathy, somnolence (2%).

Dermatologic

Hyperpigmentation (5% to 10%); alopecia, erythema multiforme, erythema nodosum, excessive dryness and fragility of the skin with anhidrosis, porphyria cutanea tarda, urticaria; rash (postmarketing).

Rash (57%); pruritus (28%); vesicular rash, vesiculobullous rash (10%); maculopapular rash, skin discoloration (8%); acne (7%); exfoliative dermatitis (5%).

EENT

Cataract, corneal thinning, lens changes (postmarketing).

Rhinitis (44%); pharyngitis (18%); ear disorder (3%).

Endocrine

Clinical syndrome similar to adrenal insufficiency.

GI

Dry mouth, cheilosis.

Nausea (98%); stomatitis (97%); vomiting (95%); anorexia (85%); diarrhea (84%); abdominal pain (72%); dyspepsia (44%); constipation (38%); dry mouth (26%); rectal disorder (25%); abdominal enlargement (23%); ileus (8%); esophagitis, hematemesis, pancreatitis (2%).

Genitourinary

Gynecomastia.

Oliguria (15%); hematuria (8%); dysuria (7%); increased BUN (3%).

Hematologic-Lymphatic

Anemia, leukopenia, myelosuppression, thrombocytopenia; aplastic anemia (postmarketing).

Myelosuppression (100%).

Hepatic

Cholestatic jaundice; hepatic veno-occlusive disease (VOD); centrilobular sinusoidal fibrosis, hepatocellular atrophy, hepatocellular necrosis (postmarketing).

Jaundice (12%); hepatic VOD after bone marrow transplantation (8%); hepatomegaly (6%).

Local

Inflammation at injection site (25%); injection site pain (15%).

Metabolic-Nutritional

Hyperbilirubinemia, hyperuricemia, hyperuricosuria.

Hypomagnesemia (77%); hyperglycemia (67%); hypokalemia (64%); hypocalcemia, hyperbilirubinemia (49%); edema (36%); ALT elevation (31%); increased creatinine (21%); hypophosphatemia (17%); alkaline phosphatase increase (15%); hyponatremia (2%).

Musculoskeletal

Back pain (23%); arthralgia (13%).

Respiratory

Interstitial pulmonary fibrosis; pneumonia (postmarketing).

Lung disorder (34%); cough (28%); dyspnea, epistaxis (25%); hiccup (18%); asthma (8%); hemoptysis, pleural effusion, sinusitis (3%); atelectasis, hypoxia (2%).

Miscellaneous

Myasthenia gravis; infection, mucositis, sepsis (postmarketing).

Fever (80%); chills (46%); pain (44%); general edema (28%); allergic reaction, chest pain (26%); graft vs host disease (18%).

Precautions

Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Use with caution, usually starting at the low end of the dosage range because of the greater frequency of decreased cardiac, hepatic, or renal function, and concomitant diseases or other drug therapy.

Hepatic Function

High doses may be associated with an increased risk of developing hepatic VOD.

Carcinogenesis

Malignant tumors have occurred in patients on busulfan therapy; this drug may be a human carcinogen.

Adrenal insufficiency

A clinical syndrome closely resembling adrenal insufficiency and characterized by anorexia, melanoderma, nausea, severe fatigue, vomiting, weakness, and weight loss has developed after prolonged therapy.

Cellular dysplasia

Busulfan may cause cellular dysplasia in many organs, in addition to the lung. Giant hyperchromatic nuclei have been reported in the adrenal glands, bone marrow, liver, lymph nodes, pancreas, and thyroid.

CV

Cardiac tamponade, which was often fatal, has been reported in a small number of children with thalassemia (2% in 1 series) who received high doses of busulfan and cyclophosphamide as the preparatory regimen for bone marrow transplantation and hematopoietic progenitor cell transplantation. Abdominal pain and vomiting preceded the tamponade in most patients.

Hyperuricemia and hyperuricosuria

May occur in patients with CML. Minimize adverse effects by increased hydration, urine alkalization, and the prophylactic administration of allopurinol.

Ovarian suppression and amenorrhea with menopausal symptoms

Commonly occurs during busulfan therapy in premenopausal patients. Busulfan has been associated with ovarian failure, including failure to achieve puberty in females.

Pulmonary effects

A rare but important complication of busulfan therapy is the development of bronchopulmonary dysplasia with pulmonary fibrosis. Symptoms have occurred within 4 mo to 10 yr after initiation of therapy. Clinically, patients report the insidious onset of cough, dyspnea, and low-grade fever. Pulmonary function studies reveal diminished diffusion capacity and decreased pulmonary compliance.

Seizures

Seizures have been reported in patients receiving high oral doses of busulfan. Risk of seizures may be reduced by prophylactic administration of phenytoin.

Overdosage

Symptoms

Bone marrow hypoplasia/aplasia, pancytopenia.

Patient Information

• Inform patients beginning therapy with busulfan of the importance of having periodic blood counts.
• Notify health care provider if any of the following occur: abrupt weakness; anorexia; congestion; fever; flank, stomach, or joint pain; persistent cough; shortness of breath; unusual bleeding or bruising; unusual fatigue; weight loss.
• Tell patients that diffuse pulmonary fibrosis is an infrequent but serious and potentially life-threatening complication of long-term busulfan therapy.
• Inform patients that some toxicities to busulfan include amenorrhea, drug hypersensitivity, dryness of the mucous membranes, infertility, and skin hyperpigmentation.
• Medication may cause appetite loss, darkening of skin, diarrhea, dizziness, fatigue, melanoderma, mental confusion, nausea, and vomiting that could be associated with a syndrome resembling adrenal insufficiency; notify health care provider if these become pronounced.
• Take medication at the same time each day.
• Extra fluid intake may be recommended.
• Contraceptive measures are recommended during therapy.
• If nausea or vomiting occurs, take the drug on an empty stomach.
• Explain the increased risk of a second malignancy to the patient.
• Instruct patients to promptly report the development of fever, sore throat, signs of local infection, bleeding from any site, or symptoms suggestive of anemia.

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