Busulfex: Drug for the treatment of chronic myelogenous leukemia

2021-06-07 01:19 PM

Busulfex (busulfan) Injection is indicated for use in combination with cyclophosphamide in a conditioning regimen prior to allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia.

Busulfex: Drug for the treatment of chronic myelogenous leukemia

Producer

Otsuka.

Ingredient

Each tube 10mL: Busulfan 60mg.

Describe

Busulfan is a bifunctional alkylating agent with the chemical formula 1,4-butanediol, dimethanesulfonate. Busulfex is administered by intravenous infusion.

Busulfex is a clear, colorless, sterile solution that comes in a 10 mL tube. Each tube of Busulfex contains 60 mg (6 mg/mL) of busulfan – the active ingredient – ​​which is a white crystalline powder with the molecular formula CH3SO2O(CH2)4OSO2CH3 and has a molecular weight of 264 g/mol. Busulfan is soluble in N, N-dimethylacetamide (DMA) 3.3 mL and polyethylene glycol 400, NF 6.7 mL. The solubility of busulfan in water is 0.1 g/L and the pH of Busulfan has been diluted to approximately 0.5 mg/mL busulfan in 0.9% sodium chloride solution or 5% dextrose solution as recommended for injection. infusion corresponds to the pH of the diluent used and is in the range of 3.4 to 3.9. Busulfex is intended to be dissolved with 0.9% sodium chloride solution or 5% dextrose solution prior to intravenous infusion.

Pharmacodynamic

Busulfan is a bifunctional alkylating agent in which two unstable methanesulfonate groups are attached at opposite ends in a 4-carbon alkyl chain. In an aqueous medium, busulfan hydrolyzes to release methanesulfonate groups. This process produces a reactive carbon ion that can alkylate DNA. Damaged DNA is believed to be the main cause of busulfan's cytotoxicity.

Pharmacokinetics

The pharmacokinetics of Busulfex were studied in 59 patients enrolled in a trial using a Busulfex-Cyclophosphamide conditioning regimen prior to allogeneic hematopoietic stem cell transplantation. Patients were given 0.8 mg/kg of Busulfex every 6 hours for a total of 16 doses over 4 days. 55 of 59 patients (93%) who received Busulfex maintained their AUC below the target range (<1500 µM•min).

The pharmacokinetics of Busulfex showed similarity between dose 9 and dose 13 as demonstrated by the reproducibility of steady-state Cmax and the low coefficient of variation of these parameters. In a pharmacokinetic study of Busulfex in 24 pediatric patients, this age pharmacokinetic (PPK) was determined to be predictive of Busulfex clearance (CL) and volume of distribution (V). . With actual body weight, PPK predicted CL and V of 4.04 L/hr/20kg (3.37 mL/min/kg; inter-patient variability 23%); and 12.8 L/20 kg (0.64 L/kg; inter-patient variability 11%).

Studies on the distribution, metabolism, and elimination of Busulfex have not been performed; however, the literature on oral busulfan can be consulted. Further, for the effect of altering pharmacological parameters see Interactions.

Distribution: Busulfan achieves concentrations in the cerebrospinal fluid that are approximately comparable to those in plasma. The fraction of binding to plasma factors, mainly to albumin, was predicted to be 32.4 ± 2.2% which is also consistent with the reactive electrophilic properties of busulfan.

Metabolism: Busulfan is primarily metabolized by conjugation with glutathione, both spontaneously and with the catalysis of glutathione S-transferase (GST). This combination is further metabolized by oxidation in the liver.

Elimination: Following administration of 14C-labelled busulfan to humans, approximately 30% of the tracer was excreted in the urine in 48 hours; Insignificant amounts were found in the feces. Failure to find the entire marker may be due to the formation of a long-lived metabolite or to nonspecific alkylation of the macromolecules.

Indications and uses

Busulfex (busulfan) Injection is indicated for use in combination with cyclophosphamide in a conditioning regimen prior to allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia.

Dosage and Administration

Note: The drug must be diluted before use.

When Busulfex is administered as part of a BuCy (busulfan-cyclophosphamide) conditioning regimen prior to bone marrow stem cell or peripheral blood stem cell replacement, the recommended dosage is as follows:

Adults (Bucy2): The usual adult dose is 0.8 mg/kg ideal body weight or actual body weight, whichever is less, administered every 6 hours for 4 days (16 doses in total). For obese, or severely obese patients, the dose of Busulfex is given based on adjusted ideal body weight.

Ideal body weight (IBW) is calculated as follows (height in cm, and weight in kg):

IBW (kg; male) = 50 + 0.91 x (height in cm – 152);

IBW (kg; female) = 45 + 0.91 x (height in cm – 152).

The adjusted ideal weight (AIBW) is calculated as follows: AIBW = IBW + 0.25 x (actual weight - IBW).

Cyclophosphamide was administered daily for 2 days at a dose of 60 mg/kg as a 1-hour infusion starting on the day of bone marrow transplantation (BMT) - 3, not earlier than 6 hours after the 16th dose of Busulfex.

Busulfex clearance is best predicted when the dose of Busulfex is based on adjusted ideal body weight. Busulfex dosing is based on actual weight, ideal body weight, or other factors that can make an important difference in the clearance of Busulfex Injection in lean, normal, and obese patients.

Busulfex is administered intravenously via a central venous catheter, given every 2 hours every 6 hours for 4 consecutive days for a total of 16 doses. All patients should be pre-administered with phenytoin because busulfan is known to cross the blood-brain barrier and induce seizures.

Phenytoin reduced plasma AUC of busulfan by 15%. The use of other anticonvulsants may produce a higher plasma AUC of busulfan and an increased risk of hepatic venous occlusion (VOD) or seizures. In cases where other anticonvulsants must be used, plasma concentrations of busulfan should be controlled (see Interactions). Antiemetics should be administered prior to the first dose of Busulfex and continued on a fixed schedule throughout the course of Busulfex. When possible, pharmacokinetic control should be considered to further target therapeutic goals.

Children: The effectiveness of Busulfex in the treatment of chronic myelogenous leukemia (CML) has not been specifically studied in children. For more information, see Use in special populations – Use in children.

Notes on preparation and infusion of drugs:

DO NOT USE POLYCARBONATE CYCLE OR POLYCARBONATE FILTERS WITH Busulfex.

An infusion set with minimal residual space (2-5 mL) should be used when administering this drug.

As with other cytotoxic agents, care should be taken when storing and preparing the Busulfex solution. Skin reactions may occur with accidental skin contact. Gloves should be used. If Busulfex or the diluted Busulfex solution comes into contact with the skin or mucous membranes, rinse the skin or mucous membranes thoroughly with water.

Busulfex is a clear, colorless solution. Drugs for parenteral use should be inspected visually for particles and discoloration prior to infusion at any time if solution and packaging can be checked. If particles are seen in the tube of Busulfex, do not use them.

Preparation for intravenous infusion: Busulfex must be diluted prior to infusion with 0.9% sodium chloride solution or 5% dextrose solution. The dilution should be 10 times the volume of Busulfex so that the final concentration of busulfan is about 0.5 mg/mL.

Calculate the dose for a 70 kg patient as follows:

(70kg body weight) x (0.8 mg/kg) ÷ (6 mg/mL) = 9.3 mL Busulfex (total dose is 56 mg)

To prepare the final infusion solution, add 9.3 mL of Busulfex to 93 mL of diluent (normal saline or 5%) as follows:

(9.3 mL Busulfex) x (10) = 93 mL diluent Add 9.3 mL Busulfex to this solution, the final concentration of busulfan is 0.54 mg/mL (9.3 mL x 6 mg). /mL ÷ 102.3 mL = 0.54 mg/mL).

The whole procedure requires strict adherence to aseptic technique, a fume hood should be used with gloves and protective clothing.

DO NOT give Busulfex into an IV bag or large volume syringe that does not contain 0.9% Sodium Chloride Solution or 5% Dextrose Solution. Always add Busulfex to the diluent, not the diluent to Busulfex. Mix thoroughly by shaking back and forth a few times. An infusion pump should be used to infuse the diluted Busulfex solution. Set the flow rate of the pump to infuse the entire prescribed dose of Busulfex in 2 hours. Before and after each infusion, flush the inside of the cathode with approximately 5 mL of 0.9% Sodium chloride solution or 5% Dextrose solution. DO NOT administer concurrently with other infusion solutions for which their compatibility is unknown. NOTE: FAST TRANSFER of Busulfex has NOT been tested and is NOT RECOMMENDED.

Warning

Busulfex should be used under the supervision of a physician experienced in hematopoietic stem cell transplantation. The management of complications during drug infusion can only be done when there are adequate and ready diagnostic and therapeutic facilities.

The following warnings pertain to the different physiological effects of Busulfex in allogeneic transplantation.

Hematologic: The most frequent serious consequence of treatment with Busulfex at the recommended dose was complete myelosuppression, which occurred in all patients. Agranulocytosis, thrombocytopenia, severe anemia, or a combination of these factors may occur. Routine blood counts, including differential white blood cell counts, and platelet counts should be monitored during treatment and until recovery is achieved. Neutrophil counts fell below 0.5x109/L at approximately 4 days post-transplant in 100% of patients treated in the Busulfex clinical trial. WBC counts were restored about 13 days after allogeneic transplantation when prophylactic G-CSF was used in the majority of patients. Thrombocytopenia (<25,000/mm3 or platelet transfusion) occurs in about 5-6 days in 98% of patients. Anemia (hemoglobin < 8.0 g/dL) occurs in 69% of patients. Antibiotic therapy and provision of platelets and red blood cells should be used when medically indicated.

Neurological: There have been reports of seizures in patients receiving high doses of oral busulfan, which produced plasma concentrations similar to those achieved with the recommended dosing of Busulfex. Despite phenytoin prophylaxis, one seizure (1/42 patients) was reported in the autologous transplant clinical trial using Busulfex. This attack occurred while taking cyclophosphamide in a conditioning regimen, 36 hours after the last dose of Busulfex. Anticonvulsant prophylaxis should be initiated prior to treatment with Busulfex. Care should be taken when administering Busulfex at the recommended dose to patients with a history of seizure disorders or head trauma or to patients taking other drugs with the potential to cause seizures.

Liver: Current literature suggests that high busulfan AUC values ​​(>1,500 µM•min) may be associated with an increased risk of developing the hepatic venous disease (HVOD). Patients who have received prior radiation therapy, more than or equal to 3 rounds of chemotherapy, or have had a prior stem cell transplant have an increased risk of developing HVOD at the recommended dose of Busulfex and treatment. Based on clinical examination and laboratory findings, hepatic venous thrombosis was diagnosed in 8% (5/61) of patients treated with Busulfex in allogeneic transplantation, resulting in death in 2/5 cases (40). %), and the overall number of deaths from HVOD in the entire study was 2/61 (3%). Three out of five patients were diagnosed with HVOD on retrospective examination that matched Jones' criteria. The reported prevalence of HVOD in the literature from randomized controlled trials is 7.7%-12%.

Cardiovascular: Cardiac tamponade has been reported in pediatric patients with thalassemia (8/400 or 2% in one episode) receiving high doses of oral busulfan and cyclophosphamide as part of a conditioning regimen for stem cell transplantation. blood formation. Six of the eight children died and two were saved by rapid pericardiocentesis. Abdominal pain and vomiting usually precede compression in most patients. No patient treated with Busulfex Injection in the clinical trial experienced cardiac tamponade.

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

Carcinogenicity, mutagenicity, impaired fertility: Busulfan is a mutagenic and chromosomal altering agent. In vitro, it was mutagenic in Salmonella typhimurium and Drosophila melanogaster. Chromosomal abnormalities caused by busulfan have been reported in vivo (rat, mouse, hamster, and human) and in vitro (rodent, human cells). Intravenous busulfan (48 mg/kg administered every two weeks of 12 mg/kg or 30% of the total dose of Busulfan on an mg/m2 basis) was associated with an increased incidence of thymic or ovarian cysts in the rat. Four cases of acute leukemia occurred in 19 patients with pancytopenia in a total of 243 patients in the study with busulfan combination as adjunctive therapy after resection of carcinoma. bronchi. The clinical appearance of leukemia is seen 5-8 years after busulfan ingestion. Busulfan is believed to be a human carcinogen.

Ovarian suppression and menopause are common in premenopausal women who are receiving long-term low-dose busulfan for the treatment of chronic myelogenous leukemia. Busulfan degrades the oocyte fluid of female rats. Busulfan induces fertility loss in male and female rats. Fertility loss, azoospermia, and testicular atrophy have also been reported in male patients.

Solvent DMA may also cause impaired fertility. Administration of a daily dose of DMA of 0.45 g/kg/day to rats for 9 days (equivalent to 44% of the daily dose of DMA contained in the recommended dose of Busulfex on an mg/m2 basis) resulted in significant reduction in spermatogenesis in rats. A single subcutaneous dose of 2.2 g/kg (27% of the total DMA dose contained in Busulfex on an mg/m2 basis) for four days after insemination terminated the pregnancies of 100% of the female hamsters. experiment.

Pregnancy: Busulfan may cause adverse effects on the fetus when administered to pregnant women. Busulfan produced teratogenic changes in the offspring of mice, rats, and rabbits when it was administered during pregnancy. Deformities and abnormalities include significant alterations in the musculoskeletal system, body weight, and size. In pregnant rats, busulfan caused infertility in both males and their offspring due to the absence of stem cells in the testes and ovaries. The solvent, DMA, can also harm an embryo when given to a pregnant woman. In rats, administration of doses of DMA 400 mg/kg/day (approximately 40% of the daily dose of DMA contained in Busulfex doses on an mg/m2 basis) during organ development also caused significant abnormalities to talk about development. Prominent abnormalities include generalized edema, cleft palate, spinal abnormalities, rib abnormalities, and severe cardiac vascular abnormalities. There are no adequate and well-controlled studies of busulfan or DMA in pregnant women. If Busulfex is used in a pregnant woman, or if the patient becomes pregnant while taking Busulfex, the patient should be informed of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking this medicine.

Overdose

An antidote to Busulfex other than hematopoietic stem cell transplantation is unknown. When hematopoietic stem cell transplantation is not possible, the recommended dose for Busulfex may cause busulfan overdose. The main toxic effects are complete bone marrow hypoplasia/regeneration and pancytopenia, but the central nervous system, liver, lungs, and gastrointestinal tract may also be affected. It is necessary to control the blood condition closely and take active supportive measures according to medical indications. Survival after a single dose of 140 mg Myleran (busulfan) Tablets has been reported in a 4-year-old child weighing 18 kg. A 2-year-old inadvertently took more than the usual dose of busulfan (2.1 mg/kg; total dose 23.3 mg/kg) before a planned bone marrow transplant without sequelae. An acute dose of 2.4 g killed a 10-year-old boy. There is a report that busulfan is dialyzable, so hemodialysis should be considered in case of overdose. Busulfan is metabolized by conjugation with glutathione, so it should be considered when co-administering glutathione.

Contraindications

Busulfex is contraindicated in patients with a history of hypersensitivity to any of the excipients.

Interactive

Itraconazole reduces busulfan clearance by up to 25% and may produce an AUC >1500 µM•min in some patients. All of the antiemetics, fluconazole, and odansetron 5-HT3 (Zofran) and granisetron (Kytril) have been administered with Busulfex.

Phenytoin increased busulfan clearance by 15% or more, possibly due to the induction of glutathione-S-transferase. Because the pharmacokinetics of Busulfex were studied in phenytoin-treated patients, the clearance of Busulfex at the recommended dose may be lower and AUC levels higher in patients not treated with phenytoin. Because busulfan is eliminated from the body through conjugation with glutathione, administration of acetaminophen before (<72 hours) or concomitantly with Busulfex may cause a decrease in busulfan clearance based on the known property that acetaminophen reduces plasma concentrations. glutathione in blood and tissues.

Adverse Effects (ADRs)

Dimethylacetamide (DMA), the solvent in the formulation of Busulfex, was studied in 1962 as a potential cancer chemotherapy drug. In a phase 1 study, the maximum tolerated dose (MTD) was 14.8 g/m2/day for 4 days. The recommended daily dose of Busulfex containing DMA is equivalent to 42% of MTD on an mg/m2 basis. The dose-limiting toxicity in the phase 1 study was hepatotoxicity with evidence of increased levels of liver transaminases (SGOT) and neurological symptoms with evidence of hallucinogens. Hallucinations typically begin one day after DMA termination and are associated with EEG changes. The lowest dose at which hallucinations can be perceived is equivalent to 1.9 times the dose used in pre-treatment with Busulfex 0.8 mg/kg every 6 hours x 16 doses. Other neurotoxic effects include somnolence, somnolence, and confusion. The exact relationship of DMA and/or concomitant medications to the observed hepatotoxicity and neurotoxicity is difficult to ascertain.

Treatment with Busulfex at the recommended and planned dose results in complete myelosuppression in 100% of patients, including granulocytopenia, thrombocytopenia, anemia, or a combination of loss of other factors. hematopoietic factor. Adverse reaction information is obtained primarily from the clinical trial (N=61) of Busulfex and data obtained with oral administration of high doses of busulfan in randomized, controlled trials known through viewing review documents.

Busulfex Clinical Trials: In the clinical trial of Busulfex Injection in allogeneic stem cell transplantation, all patients were treated with Busulfex 0.8 mg/kg infused over 2 hours, administered every 6 hours for 16 hours. dose for 4 days, combined with cyclophosphamide 60 mg/kg x 2 days. 93% of evaluable patients on this dose of Busulfex maintained an AUC lower than 1500 µM•min at dose 9, which is generally considered the level to minimize the risk of HVOD.

The next section describes clinically significant reactions that occurred in the Busulfex clinical trials, regardless of whether they were drug-related. See section ''Use in special populations – Children for information on children''.

Hematology: At the indicated doses and according to the schedule, Busulfex caused complete myelosuppression in 100% of patients. After hematopoietic stem cell infusion, a reversible neutrophil count to ≥500 cells/mm3 was present on average by day 13 of G-CSF prophylactically in the majority of the study participants. The mean number of platelet transfusions per patient in the study was 6, and the mean number of transfusions in the trial was 4. Prothrombin time prolongation was reported to occur in one patient (2%).

Gastrointestinal: Gastrointestinal toxicity occurs frequently and is generally considered to be drug-related. Some are classified as serious. Mild or moderate nausea was present in 92% of patients in the allogeneic clinical trial, and mild or moderate vomiting was present in 95% by day BMT +28, with severe nausea in 7%. The frequency of vomiting with Busulfex (BMT days -7 to -4) was 43% in the allogeneic clinical trial. Grade 3-4 stomatitis occurred in 26% of participants, and grade 3 esophagitis occurred in 2%. Grade 3-4 diarrhea was reported in 5% of all study participants, whereas diarrhea occurred in 75%. Mild or moderate constipation occurred in 38% of patients; Bowel obstruction occurred in 8% of patients and was severe in 2% of patients. 44% of patients reported mild or moderate dyspepsia. 2% of patients had mild hematemesis. Pancreatitis occurs in 2% of patients. Mild or moderate rectal disturbances occurred in 24% of patients. Severe anorexia occurred in 21% of patients and mild/moderate in 64%.

Hepatic: Hyperbilirubinemia occurred in 49% of patients in the allogeneic BMT trial. Grade 3/4 hyperbilirubinemia occurs in 30% of patients within 28 days of transplantation and is considered life-threatening in 5% of these patients. Hyperbilirubinemia was associated with graft rejection in 6 patients and with hepatic venous occlusion in 5 patients. Grade 3/4 elevations in SGPT occurred in 7% of patients. Mild or moderate elevation of alkaline phosphatase occurs in 15% of patients. Mild or moderate jaundice occurred in 12% of patients, mild or moderate hepatomegaly occurred in 6% of patients.

Hepatic Venous Disease: Hepatic Venous Obstruction (HVOD) is a potential complication of pre-transplant conditioning regimens. Based on clinical examination and laboratory results, hepatic venous occlusion was diagnosed in 8% (5/61) of all patients treated with Busulfex during allogeneic transplantation, resulting in death in 2/5 cases. 40%), and resulted in overall mortality from HVOD for the entire study of 2/61 (3%). Three out of five patients with a retrospective diagnosis of HVOD were found to fit Jones' criteria.

Graft-versus-host disease (GVHD): Graft-versus-host disease occurred in 18% of patients (11/61) with allogeneic transplants; severe is 3%, and mild or moderate is 15%. There were 3 (5%) deaths due to GVHD.

Edema: Allogeneic transplant patients present with some form of edema (79%), increased blood flow, or noted weight gain (8%); All reported manifestations are mild or moderate.

Infection/fever: 51% of patients present with one or more infectious episodes. Pneumonia was fatal in one patient (2%) and life-threatening in 3% of patients. 80% of patients reported fever; mild or moderate is 78% and severe is 3%. 46% of patients developed chills.

Cardiovascular: Tachycardia was reported in 44% of patients. In 7 patients (11%) tachycardia was first reported while taking Busulfex. Rhythmic abnormalities were mild or moderate, including arrhythmias (5%), atrial fibrillation (2%), supraventricular extrasystoles (2%), and 3rd-degree heart block (2%). Mild or moderate thrombosis occurred in 33% of patients, and all levels were related to the central venous catheter. Hypertension was reported in 36% of patients and in 3/4 in 7%. Hypotension occurred in 11% of patients and in 3/4 in 3%. Mild vasodilation (flushing, hot flashes) was reported in 25% of patients. Other cardiovascular manifestations included cardiomegaly (5%), mild ECG abnormalities (2%), grade 3/4 left heart failure in one patient (2%), and central pericardial effusion average (2%). These reactions have been reported mainly in the post-cyclophosphamide phase.

Pulmonary: Mild or moderate dyspnea occurs in 25% of patients and is severe in 2% of patients. One patient (2%) had severe rapid and deep breathing, and an additional 2 (3%) patients had the mild or moderate disease. Mild rhinitis and mild or moderate cough were reported in 44% and 28% of patients, respectively. Mild epistaxis was reported in 25% of patients. Three patients (5%) in the allogeneic study reported bleeding gums. All needed ventilator support and all died. Nonspecific interstitial fibrosis was seen at wedge biopsies during thoracoscopic video-assisted bronchoscopy in a patient in the autologous transplant study who subsequently died of respiratory failure on BMT+ 98. Several other pulmonary manifestations, reported as mild or moderate, including pharyngitis (18%), hiccups (18%), asthma (8%), atelectasis (2%), pleural effusion (3%), hypoxemia (2%), hemoptysis (3%), and sinusitis (3%).

Neurological: The most commonly reported CNS adverse reactions were insomnia (84%), anxiety (75%), dizziness (30%), and depression (23%). The severity was mild or moderate except in one patient (1%) who presented with life-threatening cerebral hemorrhage and coma as the final manifestation following multiorgan failure after HOVD. Other reactions considered serious include delirium (2%), anxiety (2%), and encephalopathy (2%). The overall frequency of confusional reactions was 11%, and 5% of patients reported hallucinations. The time to onset of confusional reactions in patients with delirium and hallucinations in the allogeneic study was when Busulfex Injection had finished. The overall frequency of coma in allogeneic clinical trials using Busulfex was 7% and of somnolence 2%. One patient (2%) treated in an autologous transplant study had a seizure response while receiving cyclophosphamide, despite phenytoin prophylaxis.

Renal: Mild or moderate elevation of creatinine in 21% of patients. BUN increased in 3% of patients and to a degree of ¾ in 2% of patients. 7% of patients presented with dysuria, 15% decreased urine output and 8% hematuria. There were 4 (7%) cases of grade ¾ hemorrhagic cystitis in the allogeneic clinical trial.

Skin: rash (57%) and pruritus (28%) reported, mostly mild. Hair loss was mild in 15% of patients and moderate in 2%. Mild vesicles were reported in 10% of patients, and the mild or moderate maculopapular rash was reported in 8%. The cystic rash was reported in 10% of patients, and exfoliative dermatitis in 5% of patients. Erythema in 2% of patients, acne in 7% of patients, and skin discoloration in 8% of patients.

Metabolism: Hyperglycemia was observed in 67% of patients and grade ¾ hyperglycemia was reported in 15% of patients. Mild or moderate hypomagnesemia in 77% of patients, mild or moderate hypokalemia in 62% of patients and severe in 2% of patients, mild or moderate hypocalcemia in 46% of patients and severe in 3% of patients, mild or moderate hypophosphatemia in 17% of patients, and hyponatremia reported in 2% of patients.

Other: Other adverse reactions reported included headache (mild or moderate 64%, severe 5%), abdominal pain (mild or moderate 69%, severe 3%), asthenia (mild or moderate 49%, severe 2%), nonspecific pain (mild or moderate 43%, severe 2%), allergic reactions (mild or moderate 24%, severe 2%), injection site inflammation (mild or moderate 25%), injection site pain (mild or moderate 15%), chest pain (mild or moderate 26%), back pain (mild or moderate 23%), myalgia (mild or moderate) 16%), arthralgia (mild or moderate 13%), and ear disorders 3%.

Death: There were two deaths by the end of day BMT+28 during allogeneic transplantation. There were 6 more deaths from day BMT+29 to day BMT+100 during allogeneic transplantation.

Post-marketing experience: The following adverse reactions (reported under MedDRA terms) have been reported with post-marketing use of Busulfex: fever, neutropenia; tumor lysis syndrome; capillary thrombosis (TMA); serious bacterial, viral (eg, hematologic) and fungal infections; infection; enamel hypoplasia. Because these reactions are reported voluntarily from an unknown number of patients, it is often not possible to determine whether a drug-induced cause is present.

Conservative

Hematology: At the recommended dose of Busulfex Injection, complete myelosuppression is common and manifests as neutropenia, thrombocytopenia, anemia, or a combination of these. Signs of localized or systemic infection or bleeding should be controlled in the patient. The patient's hematological status should be regularly assessed.

Information for patients: Patients should be informed of the increased risk of a second malignancy.

Laboratory results: Daily monitoring by total blood analysis is required in patients receiving Busulfex, including platelet counts and differences in counts until transplantation is complete. To detect hepatotoxicity, which may herald the onset of hepatic venous disease, plasma transaminases, alkaline phosphatase, and bilirubin should be assessed daily until BMT +28.

Pregnant women: see WARNINGS section

Lactation: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because busulfan has been shown to induce tumors in humans and study animals, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the patient. mom.

Use in special objects:

Children: The effectiveness of Busulfex in the treatment of chronic myelogenous leukemia (CML) in children has not been specifically studied.

An open, uncontrolled study to evaluate the pharmacokinetics of Busulfex in 24 pediatric patients receiving Busulfex as part of a conditioning regimen prior to hematopoietic stem cell transplantation for hematologic malignancies (N=15) or non-malignant (N=9). Patients ranged in age from 5 months to 16 years (mean 3 years). Give a dose of Busulfex with the aim of achieving an area under the curve (AUC) of 900-1350 µM•min with an initial dose of 0.8 mg/kg or 1.0 mg/kg (based on ABW) if the patient is similar. > 4 or ≤ 4 years old. Dosage is adjusted based on plasma concentrations after completion of dose 1.

Patients received doses of Busulfex every 6 hours and infused over 2 hours for 4 days for a total of 16 doses, followed by cyclophosphamide 50 mg/kg once daily for 4 days. After a day off, give a hematopoietic stem cells infusion. All patients were given phenytoin to prevent seizures. Target AUC (900-1350 ± 5% µMmin) was achieved at dose 1 in 71% (17/24) of patients. Steady-state pharmacokinetic testing was performed at doses 9 and 13. Busulfex concentrations were within the target range in 21 of 23 patients.

All 24 patients had neutropenia (absolute neutrophil count < 0.5 x 109/L) and thrombocytopenia (platelet transfusion or platelet count < 20,000/mm3). 79% (19/24) patients had lymphocytopenia (lymphocyte count < 0.1x109). In 23 patients, absolute neutrophil count (ANC) recovered > 0.5x109/L (mean time to recovery = BMT days + 13; recovery interval = BMT days +9 to +22) ). One patient who died on day +20 did not recover to an absolute neutrophil count (ANC) > 0.5x109/L. Four (17%) patients died during the study. Two patients died within 28 days of transplantation, one from pneumonia and capillary leak syndrome, and the other from pneumonia and veno-occlusive disease. Two patients died before day 100; one due to progressive disease and the other due to multi-organ failure.

Adverse reactions were reported in all 24 patients during the study period (day BMT-10 to day BMT+28) or the post-study follow-up period (day +29 to +100). These reactions included vomiting (100%), nausea (83%), stomatitis (79%), hepatic veno-occlusive disease (HVOD) (21%), transplant rejection disease (GVHD) (25%). , and pneumonia (21%).

Experiments based on pediatric age pharmacokinetic models have shown that 60% of pediatric patients will achieve an AUC of Busulfex between 900 and 1350 µM•min with the first dose of Busulfex as shown in the dose table above. Therapeutic control and dose adjustment after the first dose of Busulfex is recommended.

Dose adjustment based on therapeutic drug control: Guidelines for measuring the AUC of the first dose of busulfan (see Blood sampling to determine AUC), and formula for adjusting subsequent doses to achieve the desired AUC target (1125 µM•min), as follows:

Adjusted dose (mg) = Actual dose (mg) x Target AUC (µM•min)/Actual AUC (µM•min)

For example, if a patient takes a dose of 11 mg busulfan and if the measured AUC response is 800 µM•min, for a target AUC of 1125 µM•min, the target dose (in mg) would be:

Mg dose = 11 mg x 1125 M•min / 800 M•min = 15.5 mg

The dose adjustment of Busulfex can be done using the following formula and instructions:

Blood sampling to determine AUC: The calculation of AUC (µM•min) is based on taking blood samples at the following time points:

Give dose 1: 2 hours (end of infusion), 4 hours, and 6 hours (immediately before the scheduled continuation of Busulfex). Actual sampling times should be recorded.

For doses other than 1st dose: pre-infusion (baseline), 2 hours (end of infusion), 4 hours, and 6 hours (immediately prior to scheduled continuation of Busulfex).

Calculating AUC based on less than 3 specific samples above may give incorrect AUC results.

For each blood sample, draw 1 to 3 mL of blood into a Vacutainer tube coated with heparin (sodium heparin or lithium heparin). Blood samples should be placed in a wet ice tray immediately after collection and should be centrifuged (at 4°C) within 1 hour. Plasma, obtained in a suitable cryopreservation tube, was immediately frozen at -20°C. All plasma samples are sent frozen (e.g. dry ice) to the laboratory for determination of plasma busulfan concentrations.

Calculation of AUC: Calculation of Busulfex AUC can be done using the following guideline and the appropriate standard pharmacokinetic formula:

Calculation of dose AUC 1: AUC infinity = AUC0-6 hours + extrapolated AUC, where AUC0-6 hours is estimated based on the trapezoidal linear formula and extrapolated AUC can be calculated by taking the ratio of busulfan concentrations at 6 hours and elimination rate constant λz. λz must be calculated from the end-of-elimination phase of the busulfan concentration versus the time curve. A concentration of “0” should be assumed before busulfan is administered, and used to calculate the AUC.

If AUC was assessed following dose 1, steady-state AUCss (AUC0-6 h) was estimated from the region between concentrations at 2 h, 4 h, and 6 h using the trapezoidal linear formula.

Dosing instructions and blood sampling for medication monitoring: A set of infusion lines with minimal residual volume (1-3 mL) should be used for infusion to ensure that the entire prescribed dose is correctly administered. prescription and to ensure accurate blood sampling for drug control and dose adjustment.

Start the infusion of the drug solution and record the exact start time of Busulfex infusion. Collect a blood sample from a peripheral vein to avoid contamination with the drug being infused. If the blood sample is taken directly from the central venous catheter (CVC) being infused, DO NOT COLLECT THE BLOOD WHEN THE DRUG IS INQUIRIES to be sure that the blood sample at the end of the infusion is not contaminated with any other contaminants. any amount of medicine left over. After the infusion is complete (2 hours), withdraw the infusion tube and flush the CVC wire with 5 mL of physiological saline before taking a blood sample at the end of the infusion from the CVC port. Collect blood samples from a port other than the CVC port for Busulfex infusion. When recording Busulfex discontinuation time, do not include the time required to flush the inside of the catheter. Discard the infusion tube after the end of the 2-hour infusion.

See Preparation for Intravenous Infusion for detailed instructions on how to prepare the drug.

Elderly: Five of the six patients treated in the Busulfex trial were over 55 years of age (range 57-64 years). All achieved myelosuppression and engraftment.

Gender, Race: There have been no adequate studies on the dose adjustment of Busulfex based on sex and race.

Impaired Renal Function: Busulfex has not been studied in patients with impaired renal function.

Impaired hepatic function: Busulfex has not been administered to patients with impaired hepatic function.

Effects on the ability to drive and use machines: not applicable.

Other: Busulfan can cause cell dysplasia in many organs. Cytogenetic abnormalities such as giant cells and polychromosomal nuclei have been reported in the lymph nodes, pancreas, thyroid, adrenal glands, liver, lungs, and bone marrow. This cytologic dysplasia can be severe enough to cause difficulty reading the results of a smear test in the lungs, bladder, breast, and uterus.

Preservation

Store from 2oC to 8oC.

Busulfex diluted with 0.9% Sodium Chloride Solution or 5% Dextrose Solution is stable at room temperature (25oC) for 8 hours but the infusion should be completed within this time.

Busulfex diluted with 0.9% sodium chloride solution is stable under refrigeration at 2oC to 8oC for 12 hours but the infusion should be completed during this time.

Presentation and packaging

Solution for infusion: large box x 8 small boxes x 1 tube of 10mL.