Busulfex


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busulfan

Busilvex (UK), Busulfex, Myleran

Pharmacologic class: Alkylating agent

Therapeutic class: Antineoplastic

Pregnancy risk category D

FDA Box Warning

• Drug causes profound myelosuppression at recommended dosage. Give under supervision of physician experienced in allogeneic hematopoietic stem cell transplantation, cancer chemotherapy, and management of severe pancytopenia, in facility with adequate diagnostic and treatment resources.

Action

Unclear. Thought to interfere with bacterial cell-wall synthesis by cross-linking strands of DNA and disrupting RNA transcription, which causes cell to rupture and die. Exhibits minimal immunosuppressant activity.

Availability

Injection: 6 mg/ml in 10-ml ampules

Tablets: 2 mg

Indications and dosages

Chronic myelogenous leukemia

Adults: 4 to 8 mg P.O. daily until white blood cell (WBC) count decreases to 15,000/mm3; then discontinue drug until WBC count rises to 50,000/mm3, and then resume as needed.

Children: 0.06 to 0.12 mg/kg/day P.O. or 1.8 to 4.6 mg/m2/day P.O. Adjust dosage to maintain WBC count at approximately 20,000/mm3. Drug should be withheld when WBC count decreases to approximately 15,000/mm3.

Allogenic hematopoietic stem cell transplantation

Adults: 0.8 mg/kg I.V. q 6 hours for 4 days. Starting 6 hours after 16th dose of busulfan injection, give cyclophosphamide 60 mg/kg/day I.V. over 1 hour for 2 days.

Off-label uses

• Adjunctive therapy in ovarian cancer
• Bone marrow transplantation

Contraindications

• Hypersensitivity to drug
• Patients not definitively diagnosed with chronic myelogenous leukemia
• Pregnancy or breastfeeding

Precautions

Use cautiously in:
• active infections, decreased bone marrow reserve, chronic debilitating disease, depressed neutrophil and platelet counts, seizure disorders, obesity
• patients receiving concurrent myelosuppressive or radiation therapy
• females of childbearing age.

Administration

• Give oral doses on empty stomach.
• When administering I.V., withdraw dose from ampule using 5-micron filter needle. Remove filter needle and use new needle to add busulfan to diluent.
• Dilute for injection using dextrose 5% in water or normal saline solution.
• Infuse I.V. dose over 2 hours, using an infusion pump.
• Flush I.V. catheter before and after each infusion with 5 ml D5W or normal saline solution.

Be aware that drug is highly toxic and has a narrow therapeutic index.
• Maintain vigorous hydration to reduce risk of renal toxicity.
• Handle patient gently to avoid bruising.

Adverse reactions

CNS: anxiety, confusion, depression, dizziness, headache, insomnia, weakness, encephalopathy, seizures, cerebral hemorrhage, coma

CV: chest pain, hypotension, hypertension, tachycardia, ECG changes, heart block, left-sided heart failure, thrombosis, pericardial effusion, ventricular extrasystole, atrial fibrillation, arrhythmias, cardiac tamponade, cardiomegaly

EENT: cataracts, ear disorders, epistaxis, pharyngitis

GI: nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, abdominal enlargement, pancreatitis, hematemesis, dry mouth, stomatitis, anorexia

GU: dysuria, hematuria, sterility, gyne-comastia, oliguria

Hematologic: febrile neutropenia, thrombotic microangiopathy, profound myelosuppression

Hepatic: hepatitis, hepatomegaly

Metabolic: hypokalemia, hypomagnesemia, hypophosphatemia, hyperuricemia, hyperglycemia

Musculoskeletal: arthralgia, myalgia, back pain

Respiratory: hyperventilation, dyspnea, pulmonary fibrosis

Skin: pruritus, rash, acne, alopecia, erythema nodosum, exfoliative dermatitis, hyperpigmentation

Other: allergic reactions, chills, fever, injection site infection or inflammation; severe bacterial, viral, fungal infections; sepsis; tumor lysis syndrome

Interactions

Drug-drug.Anticoagulants, aspirin, nonsteroidal anti-inflammatory drugs: increased risk of bleeding

Live-virus vaccines: decreased antibody response to vaccine, increased risk of adverse reactions

Myelosuppressants: additive bone marrow depression

Nephrotoxic and ototoxic drugs (such as aminoglycosides, loop diuretics): additive nephrotoxicity and ototoxicity

Thioguanine: increased risk of hepatotoxicity

Drug-diagnostic tests.Alkaline phosphatase, aspartate aminotransferase, bilirubin, nitrogenous compounds (urea): increased levels

Hemoglobin, WBCs: decreased values

Patient monitoring

• Monitor patient closely for adequate hydration.
• Check for signs and symptoms of local or systemic infections.
• Assess for bleeding and excessive bruising.
• Evaluate oral hygiene regularly.
• Monitor CBC and WBC and platelet counts daily if patient is receiving I.V. busulfan.
• Monitor renal and hepatic function.

Know that diffuse pulmonary fibrosis ("busulfan lung") is a rare but potentially life-threatening complication, with symptom onset as late as 10 years after therapy.

Patient teaching

• Inform patient that drug doesn't cure leukemia but may induce remission.
• Advise patient to drink plenty of fluids to avoid dehydration.

Instruct patient to immediately report inability to eat or drink. Prescriber may add another drug to improve appetite.
• Inform patient that he's at increased risk for infection. Advise him to avoid contact with people with known infections and to avoid public transportation, if possible.
• Tell patient he's at increased risk for bleeding and bruising.
• Advise patient to avoid activities that can cause injury and to use soft toothbrush and electric razor to avoid gum and skin injury.
• Inform patient that he'll undergo frequent blood testing to monitor drug effects.
• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs and tests mentioned above.

busulfan

(byoo-sul-fan) ,

Busulfex

(trade name),

Myleran

(trade name)

Classification

Therapeutic: antineoplastics
Pharmacologic: alkylating agents
Pregnancy Category: D

Indications

Oral: Treatment of chronic myelogenous leukemia (CML) and bone marrow disorders. Intravenous: With cyclophosphamide as a conditioning regimen before allogenic hematopoietic progenitor cell transplantation for CML.

Action

Disrupts nucleic acid function and protein synthesis (cell-cycle phase–nonspecific).

Therapeutic effects

Death of rapidly growing cells, especially malignant ones.

Pharmacokinetics

Absorption: Rapidly absorbed from the GI tract.
Distribution: Unknown.
Metabolism and Excretion: Extensively metabolized by the liver.
Half-life: 2.5 hr.

Time/action profile (effects on blood counts)

ROUTEONSETPEAKDURATION
PO1–2 wkweeksup to 1 mo†
IVunknownunknown13 days‡
†Complete recovery may take up to 20 mo‡After administration of last dose

Contraindications/Precautions

Contraindicated in: Hypersensitivity;Failure to respond to previous courses; Obstetric / Lactation: Potential for serious side effects in fetus or infant.
Use Cautiously in: Active infections;↓ bone marrow reserve;Obese patients (base dose on ideal body weight);Other chronic debilitating diseases;Patients with childbearing potential; Geriatric: Begin therapy at lower end of dose range due to ↑ frequency of impaired cardiac, hepatic, or renal function.

Adverse Reactions/Side Effects

Incidence and severity of adverse reactions and side effects are increased with IV use

Central nervous system

    IV:
  • seizures (life-threatening)
  • cerebral hemorrhage/coma (life-threatening)
  • anxiety (most frequent)
  • confusion (most frequent)
  • depression (most frequent)
  • dizziness (most frequent)
  • headache (most frequent)
  • encephalopathy
  • mental status changes
  • weakness (most frequent)

Ear, Eye, Nose, Throat

    PO:
  • cataracts
  • IV:
  • epistaxis (most frequent)
  • pharyngitis (most frequent)
  • ear disorders

Cardiovascular

  • hepatic veno-oclusive disease (↑ allogenic transplantation)

Respiratory

    PO:
  • pulmonary fibrosis (life-threatening)
  • IV:
  • alveolar hemorrhage
  • asthma
  • atelectasis
  • cough
  • hemoptysis
  • hypoxia
  • pleural effusion
  • pneumonia
  • rhinitis
  • sinusitis

Cardiovascular

    PO:
  • cardiac tamponade (with high-dose cyclophosphamide) (life-threatening)
  • IV:
  • chest pain (most frequent)
  • hypotension (most frequent)
  • tachycardia (most frequent)
  • thrombosis (most frequent)
  • arrhythmias
  • atrial fibrillation
  • cardiomegaly
  • ECG changes
  • edema
  • heart block
  • heart failure
  • hypertension
  • pericardial effusion
  • ventricular extrasystoles

Gastrointestinal

    PO:
  • drug-induced hepatitis
  • nausea
  • vomiting
  • IV:
  • abdominal enlargement (most frequent)
  • anorexia (most frequent)
  • constipation (most frequent)
  • diarrhea (most frequent)
  • dry mouth (most frequent)
  • hematemesis (most frequent)
  • nausea (most frequent)
  • rectal discomfort (most frequent)
  • vomiting (most frequent)
  • abdominal pain
  • dyspepsia
  • hepatomegaly
  • pancreatitis
  • stomatitis

Genitourinary

  • oliguria (most frequent)
  • dysuria
  • hematuria

Dermatologic

    PO:
  • itching (most frequent)
  • rashes (most frequent)
  • acne
  • alopecia
  • erythema nodosum
  • exfoliative dermatitis
  • hyperpigmentation

Endocrinologic

    PO:
  • sterility (most frequent)
  • gynecomastia

Fluid and Electrolyte

  • hypokalemia (most frequent)
  • hypomagnesemia (most frequent)
  • hypophosphatemia (most frequent)

Hematologic

  • bone marrow depression (life-threatening)

Local

  • inflammation/pain at injection site (most frequent)

Metabolic

    PO and IV:
  • hyperuricemia
  • IV:
  • hyperglycemia (most frequent)

Musculoskeletal

  • arthralgia (most frequent)
  • myalgia (most frequent)
  • back pain

Miscellaneous

  • allergic reactions (most frequent)
  • chills (most frequent)
  • fever (most frequent)
  • infection (most frequent)

Interactions

Drug-Drug interaction

Concurrent or previous (within 72 hr) use of acetaminophen may ↓ elimination and ↑ toxicity.Concurrent use with high-dose cyclophosphamide in patients with thalassemia may result in cardiac tamponade.Concurrent use with itraconazole or phenytoin ↓ blood level effectiveness.Long-term continuous therapy with thioguanine may ↑ risk of hepatic toxicity.↑ bone marrow suppression with other antineoplastics or radiation therapy.May ↓ the antibody response to and ↑risk of adverse reactions from live-virus vaccines.

Route/Dosage

Many other regimens are used. See current protocols for up-to-date dosage
Oral (Adults) Induction—1.8 mg/m2/day or 60 mcg (0.06 mg)/kg/day until WBCs <15,000/mm3. Usual dose is 4–8 mg/day (range 1–12 mg/day). Maintenance—1–3 mg/day.
Oral (Children) 0.06–0.12 mg/kg/day or 1.8–4.6 mg/m2/day initially. Titrate dose to maintain WBC of approximately 20,000/mm3.
Intravenous (Adults) 0.8 mg/kg q 6 hr (dose based on ideal body weight or actual weight, whichever is less; in obese patients, dosage should be based on adjusted ideal body weight) for 4 days (total of 16 doses); given in combination with cyclophosphamide.

Availability

Tablets: 2 mg
Solution for injection: 6 mg/mL

Nursing implications

Nursing assessment

  • high alert: Monitor for bone marrow depression. Assess for bleeding (bleeding gums, bruising, petechiae, guaiac stools, urine, emesis) and avoid IM injections and taking rectal temperatures. Apply pressure to venipuncture sites for at least 10 min. Assess for signs of infection (fever, chills, sore throat, cough, hoarseness, lower back or side pain, difficult or painful urination) during neutropenia. Anemia may occur. Monitor for increased fatigue, dyspnea, and orthostatic hypotension. Notify health care professional if these symptoms occur.
  • Monitor intake and output ratios and daily weights. Report significant changes in totals.
    • Monitor for symptoms of gout (increased uric acid, joint pain, lower back or side pain, swelling of feet or lower legs). Encourage patient to drink at least 2 L of fluid each day. Allopurinol may be given to decrease uric acid levels. Alkalinization of urine may be ordered to increase excretion of uric acid.
    • Assess for pulmonary fibrosis (fever, cough, shortness of breath) periodically during and after therapy. Discontinue therapy at the first sign of pulmonary fibrosis. Usually occurs 8 mo–10 yr (average 4 yr) after initiation of therapy.
  • Intravenous: Premedicate patient with phenytoin before IV administration to minimize the risk of seizures.
    • Administer antiemetics before IV administration and on a fixed schedule throughout IV administration.
  • Lab Test Considerations: Monitor CBC with differential and platelet count before and weekly during therapy. The nadir of leukopenia occurs within 10–15 days and the nadir of WBC at 11–30 days. Recovery usually occurs within 12–20 wk. Notify health care professional if WBC is <15,000/mm3 or if a precipitous drop occurs. Institute thrombocytopenia precautions if platelet count is <150,000/mm3. Bone marrow depression may be severe and progressive, with recovery taking 1 mo–2 yr after discontinuation of therapy.
    • Monitor serum ALT, bilirubin, alkaline phosphatase, and uric acid before and periodically during therapy. May cause ↑ uric acid levels.
    • May cause false-positive cytology results of breast, bladder, cervix, and lung tissues.

Potential Nursing Diagnoses

Disturbed body image (Side Effects)
Risk for injury (Side Effects)
Risk for infection (Side Effects)

Implementation

  • high alert: Fatalities have occurred with chemotherapeutic agents. Before administering, clarify all ambiguous orders; double check single, daily, and course-of-therapy dose limits; have second practitioner independently double check original order, calculations, and infusion pump settings.
  • high alert: Do not confuse Myleran with Alkeran or Leukeran.
  • Oral: Administer at the same time each day. Administer on an empty stomach to decrease nausea and vomiting.
  • Intravenous Administration
  • pH: 3.4–3.9.
  • Intravenous: Prepare solution in a biologic cabinet. Wear gloves, gown, and mask while handling IV medication. Discard IV equipment in specially designated containers.
  • Intermittent Infusion: Diluent: Dilute with 10 times the volume of busulfan using 0.9% NaCl or D5W.Concentration: ≥0.5 mg/mL. When drawing busulfan from vial, use needle with 5-micron nylon filter provided, remove calculated volume from vial, remove needle and filter, replace needle and inject busulfan into diluent. Do not use polycarbonate syringes with busulfan. Only use filters provided with busulfan. Always add busulfan to diluent, not diluent to busulfan. Solution diluted with 0.9% NaCl or D5W is stable for 8 hr at room temperature and solution diluted with 0.9% NaCl is stable for 12 hr if refrigerated. Administration must be completed during this time. Solution is clear and colorless; do not administer solutions that are discolored or contain a precipitate.
  • Rate: Administer via central venous catheter over 2 hr every 6 hr for 4 days for a total of 16 doses. Use infusion pump to administer entire dose over 2 hr.
  • Y-Site Compatibility: acyclovir, amphotericin B lipid complex, amphotericin B liposome, anidulafungin, argatroban, bivalirudin, bleomycin, caspofungin, daptomycin, dexmedetomidine, diltiazem, docetaxel, ertapenem, fenoldopam, granisetron, hetastarch, hydromorphone, levofloxacin, linezolid, lorazepam, meperidine, metronidazole, milrinone, nesiritide, octreotide, ondansetron, paclitaxel, palonosetron, pancuronium, piperacillin/tazobactam, potassium acetate, quinupristin/dalfopristin, rituximab, sodium acetate, tacrolimus, tigecycline, tirofiban, trastuzumab, vasopressin, zoledronic acid
  • Y-Site Incompatibility: idarubicin, thiotepa, vecuronium, voriconazole

Patient/Family Teaching

  • Instruct patient to take medication as directed, at the same time each day, even if nausea and vomiting are a problem. Consult health care professional if vomiting occurs shortly after dose is taken. If a dose is missed, do not take at all; do not double doses.
  • Advise patient to notify health care professional if fever; sore throat; signs of infection; lower back or side pain; difficult or painful urination; sores in the mouth or on the lips; chills; dyspnea; persistent cough; bleeding gums; bruising; petechiae; or blood in urine, stool, or emesis occurs. Instruct patient to use soft toothbrush and electric razor. Caution patient not to drink alcoholic beverages or take products containing aspirin or NSAIDs.
  • Caution patient to avoid crowds and persons with known infections. Health care professional should be informed immediately if symptoms of infection occur.
  • Discuss with patient the possibility of hair loss. Explore methods of coping.
  • Instruct patient not to receive any vaccinations without advice of health care professional.
  • Advise patient to notify health care professional if unusual bleeding; bruising; or flank, stomach, or joint pain occurs. Advise patients on long-term therapy to notify health care professional immediately if cough, shortness of breath, and fever occur or if darkening of skin, diarrhea, dizziness, fatigue, anorexia, confusion, or nausea and vomiting become pronounced.
  • Inform patient of increased risk of a second malignancy with busulfan.
  • Review with patient the need for contraception during therapy. Women need to use contraception even if amenorrhea occurs.

Evaluation/Desired Outcomes

  • Decrease in leukocyte count to within normal limits.
    • Decreased night sweats.
    • Increase in appetite.
    • Increased sense of well-being. Therapy is resumed when leukocyte count reaches 50,000/mm3.

Busulfex

An injectable busulfan combined with cyclophosphamide to condition/ablate the bone marrow before allogeneic hematopoietic progenitor/stem cell transplantation in patients with CML.
 
Adverse effects
Profound myelosuppression, hepatotoxicity (raised liver enzymes), venoocclusive disease, neurotoxicity (seizures).
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References in periodicals archive ?
IV Busulfex is used in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia.
Additionally, the new formulations of intravenous busulfan, such as Busulfex (dissolved in dimethylacetamide) and a liposomal form, require clinical trials that include an evaluation of pharmacokinetic parameters, especially in children.
Orphan Medical also announced it has signed a letter of intent with Pierre Fabre Medicament, Paris, France, that would grant the company exclusive rights to market and distribute Busulfex in Europe, Argentina and South Africa.
A privately owned company Tzamal Pharma LTD has been given the right to distribute Busulfex in Israel.
The company sponsored two clinical trials of Busulfex and 100% of patients received their entire drug by injection.
Frestedt served as Manager of Clinical Affairs for Ortho Biotech, a Johnson and Johnson company; Operations Manager for Mayo Clinical Trial Services at the Mayo Clinic in Rochester, Minnesota; Medical Information Scientist for Astra Zeneca Pharmaceuticals; and Manager of Busulfex Clinical Development for Orphan Medical in Minnetonka, Minnesota.
IV Busulfex is an oncologic product marketed and sold in the United States (U.
The acquisition of IV Busulfex, a first-in-class drug therapy for conditioning prior to allogeneic hematopoietic progenitor cell transplantation, and the oncology expertise of PDL accelerates Otsuka's global oncology business," said Tatsuo Higuchi, President and Representative Director of Otsuka Pharmaceutical Co.
This process is in addition to the company's previously announced plan to sell its commercial assets, including its Cardene, Retavase and IV Busulfex products, as well as the ularitide development-stage cardiovascular product.
to advise it on the sale of the rights to Cardene, Retavase, IV Busulfex and ularitide, and related assets, in one or more transactions.
With our existing product portfolio and 2003 acquisitions, including IV Busulfex, gross 2003 revenues are expected to exceed $60 million, nearly a fourfold increase from $16 million achieved during eight months of operations ended Dec.
In July, a new vial formulation of the IV Busulfex product was launched in the United States (U.