BusulfaCedal^®

Busulfacedal® is indicated for use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia

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

Myelosuppression

The most frequent serious consequence of treatment with Busulfacedal® at the recommended dose and schedule is prolonged myelosuppression, occurring in all patients (100%). Severe granulocytopenia, thrombocytopenia, anemia, or any combination thereof may develop. Hematopoietic progenitor cell transplantation is required to prevent potentially fatal complications of the prolonged myelosuppression.

Monitor complete blood counts, including white blood cell differentials, and quantitative platelet counts daily during treatment and until engraftment is demonstrated. Absolute neutrophil counts dropped below 0.5×10 /L at a median of 4 days post-transplant in 100% of patients treated in the Busulfacedal® clinical trial. The absolute neutrophil count recovered at a median of 13 days following allogeneic transplantation when prophylactic filgrastim was used in the majority of patients. Thrombocytopenia (less than 25,000/mm or requiring platelet transfusion) occurred at a median of 5-6 days in 98% of patients. Anemia (hemoglobin less than 8.0 g/dL) occurred in 69% of patients. Use antibiotic therapy and platelet and red blood cell support when medically indicated.

Seizures

Seizures have been reported in patients receiving high-dose oral busulfan at doses producing plasma drug levels similar to those achieved following the recommended dosage of Busulfacedal®. Despite prophylactic therapy with phenytoin, one seizure (1/42 patients) was reported during an autologous transplantation clinical trial of Busulfacedal®. This episode occurred during the cyclophosphamide portion of the conditioning regimen, 36 hours after the last Busulfacedal® dose. Initiate phenytoin therapy or any other alternative anti-convulsant prophylactic therapy (e.g., benzodiazepines, valproic acid or levetiracetam) prior to Busulfacedal® treatment. Use caution when administering the recommended dose of Busulfacedal® to patients with a history of a seizure disorder or head trauma or who are receiving other potentially epileptogenic drugs.

Hepatic Veno-Occlusive Disease (HVOD)

Current literature suggests that high busulfan area under the plasma concentration verses time curve (AUC) values (greater than 1,500 μM∙min) may be associated with an increased risk of developing HVOD. Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or a prior progenitor cell transplant may be at an increased risk of developing HVOD with the recommended Busulfacedal® dose and regimen. Based on clinical examination and laboratory findings, HVOD was diagnosed in 8% (5/61) of patients treated with Busulfacedal® in the setting of allogeneic transplantation, was fatal in 2/5 cases (40%), and yielded an overall mortality from HVOD in the entire study population of 2/61 (3%). Three of the five patients diagnosed with HVOD were retrospectively found to meet the Jones’ criteria. The incidence of HVOD reported in the literature from the randomized, controlled trials was 7.7%-12%. Monitor serum transaminases, alkaline phosphatase, and bilirubin daily through BMT Day +28 to detect hepatotoxicity, which may herald the onset of HVOD.

Embryo-fetal Toxicity

Busulfacedal ® can cause fetal harm when administered to a pregnant woman based on animal data. Busulfan was teratogenic in mice, rats, and rabbits. The solvent, DMA, may also cause fetal harm when administered to a pregnant woman based on findings in animals. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during and after treatment with Busulfacedal®.

Cardiac Tamponade

Cardiac tamponade has been reported in pediatric patients with thalassemia (8/400 or 2% in one series) who received high doses of oral busulfan and cyclophosphamide as the preparatory regimen for hematopoietic progenitor cell transplantation. Six of the eight children died and two were saved by rapid pericardiocentesis. Abdominal pain and vomiting preceded the tamponade in most patients. Monitor for signs and symptoms, promptly evaluate and treat if cardiac tamponade is suspected.

Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia with pulmonary fibrosis is a rare but serious complication following chronic busulfan therapy. The average onset of symptoms is 4 years after therapy (range 4 months to 10 years).

Cellular Dysplasia

Busulfacedal® may cause cellular dysplasia in many organs. Cytologic abnormalities characterized by giant, hyperchromatic nuclei have been reported in lymph nodes, pancreas, thyroid, adrenal glands, liver, lungs and bone marrow. This cytologic dysplasia may be severe enough to cause difficulty in the interpretation of exfoliative cytologic examinations of the lungs, bladder, breast and the uterine cervix.

Busulfacedal® administration should be supervised by a physician experienced in conditioning treatment prior to haematopoietic progenitor cell transplantation.

Busulfacedal® is administered prior to the haematopoietic progenitor cell transplantation (HPCT).

Dosage:

Initial Dosing Information

Administer Busulfacedal® 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:

Busulfacedal® 0.8 mg per kg (ideal body weight or actual body weight, whichever is lower) intravenously via a central venous catheter as two‑hour infusion every six hours for four consecutive days for a total of 16 doses (Days -7, -6, -5 and -4).

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 dose of Busulfacedal® (Days -3 and -2).

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 Busulfacedal®. Administer anticonvulsants 12 hours prior to Busulfacedal ® to 24 hours after the last dose of Busulfacedal®. Administer antiemetics prior to the first dose of Busulfacedal® and continue on a fixed schedule through Busulfacedal® administration. Busulfacedal® clearance is best predicted when the Busulfacedal® dose is administered based on adjusted ideal body weight. Dosing Busulfacedal® based on actual body weight, ideal body weight or other factors can produce significant differences in Busulfacedal® clearance among lean, normal and obese patients. Calculate ideal body weight (IBW) as follows (height in cm, and weight in kg): 

Men: IBW (kg)=50+0.91× (height in cm -152)

Women: IBW (kg)=45+0.91× (height in cm -152)

For obese or severely obese patients, base Busulfacedal ® dosing on adjusted ideal body weight (AIBW): AIBW= IBW +0.25× (actual weight -IBW).

Preparation for Intravenous Administration

Busulfacedal® is incompatible with polycarbonate. Do not use any infusion components (Syringes, filter needles, intravenous tubing, etc.) containing polycarbonate with Busulfacedal®. Use an administration set with minimal residual hold-up volume (2 mL to 5 mL) for product administration.Busulfacedal® 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 Busulfacedal®, 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) × (0.8 mg per kg) ÷ (6 mg per mL) =9.3 mL Busulfacedal® (56 mg total dose).

To prepare the final solution for infusion, add 9.3 mL of Busulfacedal® to 93 mL of diluent (normal saline or D5W) as calculated below:

(9.3 mL Busulfacedal®) × (10) =93 mL of either diluent plus the 9.3 mL of Busulfacedal® to yield a final concentration of busulfan of 0.54 mg per mL (9.3 mL × 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 Busulfacedal® to the diluent, not the diluent to the Busulfacedal®. Mix thoroughly by inverting several times. Discard the unused portion. Infusion pumps should be used to administer the diluted Busulfacedal® solution. Set the flow rate of the pump to deliver the entire prescribed Busulfacedal® 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.

WARNING: RAPID INFUSION OF BUSULFACEDAL® HAS NOT BEEN TESTED AND IS NOT RECOMMENDED.

>10%:

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

<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
• Reporting of suspected adverse reactions
• Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Please report any adverse drug reactions via contacting Cedal Nano.

OVERDOSAGE:

There is no known antidote to Busulfacedal® other than hematopoietic progenitor cell transplantation. In the absence of hematopoietic progenitor cell transplantation, the recommended dosage for Busulfacedal® would constitute an overdose of busulfan. The principal toxic effect is profound bone marrow hypoplasia/aplasia and pancytopenia, but the central nervous system, liver, lungs, and gastrointestinal tract may be affected. Monitor hematologic status closely and institute vigorous supportive measures as medically indicated. Survival after a single 140 mg dose of Myleran Tablets in an 18 kg, 4‑year old child has been reported. Inadvertent administration of a greater than normal dose of oral busulfan (2.1 mg per kg; total dose of 23.3 mg per kg) occurred in a 2‑year old child prior to a scheduled bone marrow transplant without sequelae. An acute dose of 2.4 g was fatal in a 10‑year old boy. There is one report that busulfan is dialyzable, thus dialysis should be considered in the case of overdose.

Drugs that Decrease Busulfacedal ® Clearance

Itraconazole decreases busulfan clearance by up to 25%. Metronidazole decreases the clearance of busulfan to a greater extent than does itraconazole; metronidazole coadministration has been associated with increased busulfan toxicity. Fluconazole (200 mg) has been used with Busulfacedal®.

Decreased clearance of busulfan was observed with concomitant use with deferasirox. The mechanism of this interaction is not fully elucidated. Discontinue iron chelating agents well in advance of administration of Busulfacedal® to avoid increased exposure to busulfan. Because busulfan is eliminated from the body via conjugation with glutathione, use of acetaminophen prior to (less than 72 hours) or concurrent with Busulfacedal® may result in reduced busulfan clearance based upon the known property of acetaminophen to decrease glutathione levels in the blood and tissues.

Drugs that Increase Busulfacedal ® Clearance

Phenytoin increases the clearance of busulfan by 15% or more, possibly due to the induction of glutathione-S-transferase. Since the pharmacokinetics of Busulfacedal® were studied in patients treated with phenytoin, the clearance of Busulfacedal® at the recommended dose may be lower and exposure (AUC) higher in patients not treated with phenytoin.

• Pregnancy

Busulfacedal® 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 Busulfacedal® dose on a mg/m 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 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

• Breastfeeding

It is not known whether Busulfacedal® is present in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for busulfan in human and animal studies, discontinue breastfeeding during treatment with Busulfacedal®.

• Fertility Females

Busulfacedal® can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Busulfacedal® and for 6 months following cessation of therapy.

• Fertility Males

Busulfacedal® 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 Busulfacedal® and for 3 months after cessation of therapy.

• Infertility Females

Ovarian suppression and amenorrhea commonly occur in premenopausal women undergoing chronic, low-dose busulfan therapy for chronic myelogenous leukemia. Busulfacedal® may cause temporary or permanent infertility in prepubertal girls or in females of child-bearing potential treated with high-dose Busulfacedal® in the conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation.

• Infertility Males

Sterility, azoospermia, and testicular atrophy have been reported in male patients. Cases of thrombotic microangiopathy after hematopoietic cell transplantation (HCT), including fatal cases, have been reported in high-dose conditioning regimens in which busulfan was administered in combination with another conditioning treatment.

• Busulfacedal® is incompatible with polycarbonate. Do not use any infusion components (syringes, filter needles, intravenous tubing, etc.) containing polycarbonate with Busulfacedal®.
• Unopened vials of Busulfacedal® must be stored under refrigerated conditions between 2°C to 8°C (36°F to 46°F). Discard unused portion.Busulfacedal® 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. Busulfacedal® 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.