PMS BUSULFAN

Busulfan is a bifunctional alkylating agent, having a selective immunosuppressive effect on bone marrow.

It is not a structural analog of the nitrogen mustards.

It has been used in the palliative treatment of chronic myeloid leukemia (myeloid leukemia, chronic), but although symptomatic relief is provided, no permanent remission is brought about.

According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), busulfan is listed as a known carcinogen.

For use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous (myeloid, myelocytic, granulocytic) leukemia (FDA has designated busulfan as an orphan drug for this use).

It is also used as a component of pretransplant conditioning regimens in patients undergoing bone marrow transplantation for acute myeloid leukemia and nonmalignant diseases.

Busulfan is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer.

Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells.

They stop tumor growth by cross-linking guanine bases in DNA double-helix strands.

• directly attacking DNA.

This makes the strands unable to uncoil and separate.

As this is necessary in

DNA replication, the cells can no longer divide.

In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn leads to a miscoding of DNA.

Alkylating agents are cell cycle-nonspecific and work by three different mechanisms, all of which achieve the same end result.

• disruption of DNA function and cell death.

Overexpression of

MGST2, a glutathione s-transferase, is thought to confer resistance to busulfan.

The role of

MGST2 in the metabolism of busulfan is unknown however.

Completely absorbed from the gastrointestinal tract.

Busulfan is a small, highly lipophilic molecule that crosses the blood-brain-barrier.

The absolute bioavailability, if a single 2 mg Intravenous bolus injection is given to adult patients, is 80% ± 20%.

In children (1.5-6 years old), the absolute bioavailability was 68% ± 31%.

When a single oral dose is given to patients, the area under the curve (AUC) was 130 ng•hr/mL.

The peak plasma concentration when given

Oral is 30 ng/mL (after dose normalization to 2 mg).

It takes 0.9 hours to reach peak plasma concentration after dose normalization to 4 mg.

Busulfan is extensively metabolizes in the hepatic.

Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and by glutathione S-transferase (GST) catalysis.

GSTA1 is the primary GST isoform that facilitates the the metabolism of busulfan.

Other GST isoforms that are also involved are GSTM1 and GSTP1.

At least 12 metabolites have been identified among which tetrahydrothiophene, tetrahydrothiophene 12-oxide, sulfolane, and 3-hydroxysulfolane were identified.

These metabolites do not have cytotoxic activity.

Following administration of 14C.

• labeled busulfan to humans, approximately 30% of the radioactivity was excreted into the urine over 48 hours; negligible amounts were recovered in feces.

Less than 2% of the administered dose is excreted in the urine unchanged within 24 hours.

Elimination of busulfan is independent of renal function.

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Signs of overdose include allergic reaction, unusual bleeding or bruising, sudden weakness or unusual fatigue, persistent cough, congestion, or shortness of breath; flank, stomach or joint pain; pronounced nausea, vomiting, diarrhea, dizziness, confusion, or darkening of the skin, chills, fever, collapse, and loss of consciousness.

Busulfan is contraindicated in patients with a history of hypersensitivity to any of its components.

Pre-medicate with anticonvulsants (e.g. benzodiazepines, phenytoin, valproic acid or levetiracetam) and antiemetic Dilute and administer as intravenous infusion.

Do not administer as intravenous push or bolus Recommended adult dose: 0.8 mg per kg of ideal body weight or actual body weight, whichever is lower, administered intravenously via a central venous catheter as a two-hour infusion every six hours for four consecutive days for a total of 16 doses 2.1 Initial Dosing Information.

• Administer busulfan injection in combination with cyclophosphamide as a conditioning regimen prior to bone marrow or peripheral blood progenitor cell replacement.

For patients weighing more than 12 kg, the recommended doses are: o Busulfan injection 0.8 mg per kg (ideal body weight or actual body weight, whichever is lower) intravenously via a central venous catheter as a two-hour infusion every six hours for four consecutive days for a total of 16 doses (Days -7, -6, -5 and -4). o Cyclophosphamide 60 mg per kg intravenously as a one-hour infusion on each of two days beginning no sooner than six hours following the 16 th dose of busulfan injection (Days -3 and -2). o Administer hematopoietic progenitor cells on Day 0.

• Premedicate patients with anticonvulsants (e.g., benzodiazepines, phenytoin, valproic acid or levetiracetam) to prevent seizures reported with the use of high dose busulfan injection.

Administer anticonvulsants 12 hours prior to busulfan injection to 24 hours after the last dose of busulfan injection.

• Administer antiemetics prior to the first dose of busulfan injection and continue on a fixed schedule through busulfan injection administration.

• Busulfan injection clearance is best predicted when the busulfan injection dose is administered based on adjusted ideal body weight.

Dosing busulfan injection based on actual body weight, ideal body weight or other factors can produce significant differences in busulfan injection clearance among lean, normal and obese patients. o Calculate ideal body weight (IBW) as follows (height in cm and weight in kg): Men: IBW (kg) = 50+0.91x (height in cm -152) Women: IBW (kg) = 45+0.91x (height in cm -152) o For obese or severely obese patients, base busulfan injection dosing on adjusted ideal body weight (AIBW): AIBW= IBW + 0.25x (actual weight -IBW). 2.2 Preparation and Administration Precautions Busulfan injection is incompatible with polycarbonate.

Do not use any infusion components (syringes, filter needles, intravenous tubing, etc). containing polycarbonate with busulfan injection.

Use an administration set with minimal residual hold-up volume (2 mL to 5 mL) for product administration.

Busulfan injection is a cytotoxic drug.

Follow applicable special handling and disposal procedures.

Skin reactions may occur with accidental exposure.

Use gloves when preparing busulfan injection.

If busulfan injection or diluted busulfan injection solution contacts the skin or mucosa, wash the skin or mucosa thoroughly with water.

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration whenever the solution and container permit.

Do not use if particulate matter is seen in the busulfan injection vial. 2.3 Preparation for Intravenous Administration Busulfan injection must be diluted prior to intravenous infusion with either 0.9% Sodium Chloride Injection, USP (normal saline) or 5% Dextrose Injection, USP (D5W).

The diluent quantity should be 10 times the volume of busulfan injection, so that the final concentration of busulfan is approximately 0.5 mg per mL.

Calculation of the dose for a 70 kg patient would be performed as follows: (70 kg patient) x (0.8 mg per kg) ÷ (6 mg per mL) = 9.3 mL busulfan injection (56 mg total dose).

To prepare the final solution for infusion, add 9.3 mL of busulfan injection to 93 mL of diluent (normal saline or D5W) as calculated below: (9.3 mL busulfan injection) x = 93 mL of either diluent plus the 9.3 mL of busulfan injection to yield a final concentration of busulfan of 0.54 mg per mL (9.3 mL x 6 mg per mL ÷ 102.3 mL =0.54 mg per mL).

All transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical laminar flow safety hood while wearing gloves and protective clothing.

Always add the busulfan injection to the diluent, not the diluent to the busulfan injection.

Mix thoroughly by inverting several times.

Discard unused portion.

Infusion pumps should be used to administer the diluted busulfan injection solution.

Set the flow rate of the pump to deliver the entire prescribed busulfan injection dose over two hours.

Prior to and following each infusion, flush the indwelling catheter line with approximately 5 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.

DO NOT infuse concomitantly with another intravenous solution of unknown compatibility.

RAPID INFUSION OF BUSULFAN INJECTION HAS NOT BEEN TESTED AND IS NOT RECOMMENDED.

Busulfan injection is packaged as a clear, colorless, sterile solution in 10 mL single-dose clear glass vials. 60 mg per 10 mL (6 mg/mL) 10 mL Single-Dose Vials Packaged in a Carton of 8 NDC 55150-395-08 16.2 Storage and Handling Unopened vials of busulfan injection must be stored under refrigerated conditions between 2°C to 8°C (36°F to 46°F).

Discard unused portion.

Busulfan injection diluted in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP is stable at room temperature (25°C) for up to 8 hours but the infusion must be completed within that time.

Busulfan injection diluted in 0.9% Sodium Chloride Injection, USP is stable at refrigerated conditions (2°C to 8°C) for up to 12 hours but the infusion must be completed within that time.

Busulfan injection is a cytotoxic drug.

Follow applicable special handling and disposal procedures 1.

The vial stopper is not made with natural rubber latex.

Busulfan can cause fetal harm when administered to a pregnant woman based on animal data.

Busulfan was teratogenic in mice, rats, and rabbits following administration during organogenesis.

The solvent, DMA, may also cause fetal harm when administered to a pregnant woman.

In rats, DMA doses of approximately 40% of the daily dose of DMA in the busulfan dose on a mg/m 2 basis given during organogenesis caused significant developmental anomalies.

There are no available human data informing the drug-associated risk.

Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated populations are unknown.

However, the background risk in the U.S. general population of major birth defects is to 4% and of miscarriage is to 20% of clinically recognized pregnancies.

Following administration during organogenesis in animals, busulfan caused malformations and anomalies, including significant alterations in the musculoskeletal system, body weight gain, and size.

In pregnant rats, busulfan produced sterility in both male and female offspring due to the absence of germinal cells in the testes and ovaries.

The solvent, N,N.

• dimethylacetamide (DMA), administered to rats at doses of 400 mg/kg/day (about 40% of the daily dose of DMA in the busulfan dose on a mg/m 2 basis) during organogenesis caused significant developmental anomalies.

The most striking abnormalities included anasarca, cleft palate, vertebral anomalies, rib anomalies, and serious anomalies of the vessels of the heart.

Females and Males of Reproductive Potential Contraception Females Busulfan can cause fetal harm when administered to a pregnant woman.

Advise females of reproductive potential to use effective contraception during treatment with busulfan and for 6 months following cessation of therapy.

Busulfan may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities.

Males with female sexual partners of reproductive potential should use effective contraception during treatment with busulfan and for 3 months after cessation of therapy.

Ovarian suppression and amenorrhea commonly occur in premenopausal women undergoing chronic, low-dose busulfan therapy for chronic myelogenous leukemia.

Busulfan may cause temporary or permanent infertility in prepubertal girls or in females of child-bearing potential treated with high-dose busulfan in the conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation.

Sterility, azoospermia, and testicular atrophy have been reported in male patients.

The effectiveness of busulfan in the treatment of CML has not been specifically studied in pediatric patients.

An open-label, uncontrolled study evaluated the pharmacokinetics of busulfan in 24 pediatric patients receiving busulfan as part of a conditioning regimen administered prior to hematopoietic progenitor cell transplantation for a variety of malignant hematologic (N=15) or non-malignant diseases (N=9).

Patients ranged in age from 5 months to 16 years (median 3 years).

Busulfan dosing was targeted to achieve an area under the plasma concentration curve (AUC) of to 1350 µM•min with an initial dose of 0.8 mg per kg or 1.0 mg per kg (based on Actual Body Weight (ABW)) if the patient was greater than 4 or less than or equal to 4 years, respectively.

The dose was adjusted based on plasma concentration after completion of dose 1.

Patients received busulfan doses every six hours as a two-hour infusion over four days for a total of 16 doses, followed by cyclophosphamide 50 mg per kg once daily for four days.

After one rest day, hematopoietic progenitor cells were infused.

All patients received phenytoin as seizure prophylaxis.

The target

AUC (900 to 1350±5% µM•min) for busulfan was achieved at dose in 71% (17/24) of patients.

Steady state pharmacokinetic testing was performed at dose and 13.

Busulfan levels were within the target range for of 23 evaluable patients.

All 24 patients experienced neutropenia (absolute neutrophil count (ANC) less than 0.5x10 9 /L) and thrombocytopenia (platelet transfusions or platelet count less than 20,000/mm 3 ).

Seventy-nine percent (19/24) of patients experienced lymphopenia (absolute lymphocyte count less than 0.1x10 9 ).

In 23 patients, the ANC recovered to greater than 0.5x10 9 /L (median time to recovery = BMT day +13; range = BMT day +9 to +22).

One patient who died on day +20 had not recovered to an ANC >0.5x10 9 /L. Four (17%) patients died during the study.

Two patients died within 28 days of transplant; one with pneumonia and capillary leak syndrome, and the other with pneumonia and veno-occlusive disease.

Two patients died prior to day 100; one due to progressive disease and one due to multi-organ failure.

Adverse reactions were reported in all 24 patients during the study period (BMT day -10 through BMT day +28) or post.

• study surveillance period (day +29 through +100).

These included vomiting (100%), nausea (83%), stomatitis (79%), HVOD (21%), graft-versus host disease (GVHD) (25%), and pneumonia (21%).

Based on the results of this 24-patient clinical trial, a suggested dosing regimen of busulfan in pediatric patients is shown in the following dosing nomogram: Busulfan Dosing Nomogram Patient’s Actual Body Weight (ABW) Busulfan Dosage less than or equal to 12 kgs 1.1 (mg per kg) greater than 12 kgs 0.8 (mg per kg) Simulations based on a pediatric population pharmacokinetic model indicate that approximately 60% of pediatric patients will achieve a target busulfan exposure (AUC) between to 1350 µM•min with the first dose of busulfan using this dosing nomogram.

Therapeutic drug monitoring and dose adjustment following the first dose of busulfan is recommended.

Dose Adjustment Based on Therapeutic Drug Monitoring Instructions for measuring the AUC of busulfan at dose and the formula for adjustment of subsequent doses to achieve the desired target AUC (1125 μM•min), are provided below.

Adjusted dose (mg) = Actual Dose (mg) x Target AUC (µM•min)/Actual AUC (µM•min) For example, if a patient received a dose of 11 mg busulfan and if the corresponding AUC measured was 800 μM•min, for a target AUC of 1125 µM•min, the target mg dose would be: Mg dose =11 mg x 1,125 µM•min /800 µM•min =15.5 mg Busulfan dose adjustment may be made using this formula and instructions below.

Blood Sample Collection for AUC Determination Calculate the AUC (µM•min) based on blood samples collected at the following time points: For dose 1:2 hr (end of infusion), 4 hr and 6 hr (immediately prior to the next scheduled busulfan administration).

Actual sampling times should be recorded.

For doses other than dose 1: Pre-infusion (baseline), 2 hr (end of infusion), 4 hr and 6 hr (immediately prior to the next scheduled busulfan administration).

AUC calculations based on fewer than the three specified samples may result in inaccurate AUC determinations.

For each scheduled blood sample, collect one to three mL of blood into heparinized (Na or Li heparin) Vacutainer ® tubes.

The blood samples should be placed on wet ice immediately after collection and should be centrifuged (at 4°C) within one hour.

The plasma, harvested into appropriate cryovial storage tubes, is to be frozen immediately at -20°C. All plasma samples are to be sent in a frozen state (i.e., on dry ice) to the assay laboratory for the determination of plasma busulfan concentrations.

AUC calculations may be made using the following instructions and appropriate standard pharmacokinetic formula: Dose 1 AUC infinity Calculation: AUC infinity = AUC 0-6 hr +AUC extrapolated, where AUC 0-6hr is to be estimated using the linear trapezoidal rule and AUC extrapolated can be computed by taking the ratio of the busulfan concentration at Hour and the terminal elimination rate constant, λ z.The λ z must be calculated from the terminal elimination phase of the busulfan concentration vs. time curve.

A “0” pre-dose busulfan concentration should be assumed, and used in the calculation of AUC.

If the AUC is assessed subsequent to Dose 1, steady-state AUC ss (AUC 0-6hr ) is to be estimated from the trough, 2 hr, 4 hr and 6 hr concentrations using the linear trapezoidal rule.

Instructions for Drug Administration and Blood Sample Collection for Therapeutic Drug Monitoring Use an administration set with minimal residual hold up (priming) volume (1 to 3 mL) for drug infusion to ensure accurate delivery of the entire prescribed dose and to ensure accurate collection of blood samples for therapeutic drug monitoring and dose adjustment.

Prime the administration set tubing with drug solution to allow accurate documentation of the start time of busulfan infusion.

Collect the blood sample from a peripheral IV line to avoid contamination with infusing drug.

If the blood sample is taken directly from the existing central venous catheter (CVC), DO NOT COLLECT THE BLOOD SAMPLE WHILE THE DRUG IS INFUSING to ensure that the end of infusion sample is not contaminated with any residual drug.

At the end of infusion (2 hr), disconnect the administration tubing and flush the CVC line with 5 mL of normal saline prior to the collection of the end of infusion sample from the CVC port.

Collect the blood samples from a different port than that used for the busulfan infusion.

When recording the busulfan infusion stop time, do not include the time required to flush the indwelling catheter line.

Discard the administration tubing at the end of the two-hour infusion.

Clinical studies of busulfan did not include sufficient numbers of subjects aged and over to determine whether they respond differently from younger subjects.