Busulfan accord

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BUSULFAN ACCORD

Composition:

Active substance: busulfan;

1 ml of concentrate contains 6 mg of busulfan;

Excipients: dimethylacetamide, polyethylene glycol 400.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colourless solution in a clear glass vial. When observed under appropriate lighting conditions, it should be practically free from foreign particles.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Antineoplastic agents. Alkylating agents. Alkylsulfonates. Busulfan.

ATC code L01A B01.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Busulfan is a potent cytotoxic agent and a bifunctional alkylating agent.

In an aqueous environment, the release of methanesulfonate groups leads to the formation of carbonium ions, which can cause DNA alkylation. This process is considered a key biological mechanism underlying the cytotoxic effects of this agent.

Clinical Efficacy and Safety

Busulfan in Combination with Cyclophosphamide

Adults

Data on the safety and efficacy of busulfan in combination with cyclophosphamide in the BuCy2 regimen prior to standard allogeneic and/or autologous hematopoietic stem cell transplantation (HSCT) were obtained from two clinical studies (OMC-BUS-4 and OMC-BUS-3).

Two prospective, time-limited, open-label, uncontrolled phase II studies were conducted in a group of patients with hematological disorders, most of whom had advanced-stage disease.

Patients included in the studies had acute leukemia in first remission, during first or subsequent relapse, in first remission (high risk), or after failed induction; chronic myeloid leukemia in chronic or advanced phase; primary refractory or relapsed/refractory Hodgkin’s disease or non-Hodgkin’s lymphoma; and myelodysplastic syndrome.

Patients received busulfan 0.8 mg/kg body weight as an infusion every 6 hours for a total of 16 doses, followed by cyclophosphamide 60 mg/kg body weight once daily for two days (BuCy2 regimen). The primary efficacy endpoints in these studies were bone marrow suppression, engraftment, relapse, and survival.

In both studies, all patients received busulfan according to the 16/16 dose schedule. No patient was withdrawn from the study due to adverse effects related to busulfan.

All patients experienced profound bone marrow suppression. The time to achieve an absolute neutrophil count (ANC) > 0.5 x 10⁹/L was 13 days (range: 9–29 days) in patients after allogeneic transplantation (OMC-BUS-4) and 10 days (range: 8–19 days) in patients after autologous transplantation (OMC-BUS-3). All evaluable patients proceeded to transplantation. No primary or secondary graft rejection was observed. All-cause mortality and non-relapse mortality at more than 100 days after allogeneic transplantation were 13% (8/61) and 10% (6/61), respectively. No deaths were observed in autologous transplant recipients during the same period.

Children and Adolescents

Data on the safety and efficacy of busulfan in combination with cyclophosphamide in the BuCy4 regimen or with melphalan in the BuMel regimen prior to standard allogeneic and/or autologous HSCT were obtained from the clinical study F60002 IN 101 G0.

Patients received the dosing regimen described in the section "Dosage and Administration".

All patients experienced profound bone marrow suppression. The time to achieve an ANC > 0.5 x 10⁹/L was 21 days (range: 12–47 days) in patients after allogeneic transplantation and 11 days (range: 10–15 days) in patients after autologous transplantation. Engraftment occurred in all children.

No primary or secondary graft rejection was observed. Full chimerism was observed in 93% of patients after allogeneic transplantation. No treatment-related deaths were reported within the first 100 days and up to one year after transplantation.

Busulfan in Combination with Fludarabine (FB)

Adults

Data on the safety and efficacy of busulfan in combination with FB prior to allogeneic HSCT were derived from a literature review of seven published studies involving 731 patients with myeloid and lymphoid malignancies, in which intravenous busulfan was administered once daily instead of four times daily.

Patients received a conditioning regimen based on fludarabine followed by a single daily dose of busulfan at 3.2 mg/kg for 2 or 3 consecutive days. The total busulfan dose per patient ranged from 6.4 mg/kg to 9.6 mg/kg. The combined FB regimen allowed sufficient myeloablation, with conditioning intensity modulated by varying the number of days of busulfan infusion. In most studies, rapid and complete engraftment was achieved in 80–100% of patients. Most publications reported full chimerism on day +30 in 90–100% of patients. Long-term outcomes confirmed sustained efficacy without unexpected effects.

Data from a recently completed multicenter, prospective phase II study involving 80 patients aged 18 to 65 years with various hematological malignancies who underwent FB allogeneic HSCT (3-day busulfan regimen) demonstrated the feasibility of reduced-intensity conditioning. In this study, all but one patient received the graft, with engraftment occurring on average 15 (10–23) days after allogeneic HSCT. The cumulative incidence of neutrophil recovery by day 28 was 98.8% (95% CI: 85.7–99.9%). Platelet engraftment occurred on average 9 (range: 1–16) days after allogeneic HSCT.

The overall two-year survival (OS) was 61.9% (95% CI: 51.1–72.7%). At two years, the cumulative incidence of non-relapse mortality (NRM) was 11.3% (95% CI: 5.5–19.3%), and the cumulative incidence of relapse or progression after allogeneic HSCT was 43.8% (95% CI: 31.1–55.7%). The Kaplan-Meier estimate for disease-free survival (DFS) at two years was 49.9% (95% CI: 32.6–72.7).

Pharmacokinetics

The pharmacokinetics of busulfan have been studied. The information presented on metabolism and elimination is based on studies of oral busulfan administration.

Pharmacokinetics in Adults

Absorption

The pharmacokinetics of intravenous busulfan were studied in 124 patients after a two-hour intravenous infusion, with a total of 16 doses administered over 4 days. After intravenous infusion, the bioavailability of the busulfan dose is immediate and complete. Comparable blood concentration profiles were observed when comparing plasma concentrations in adult patients receiving busulfan at 1 mg/kg orally and 0.8 mg/kg intravenously. In a population pharmacokinetic analysis conducted in 102 patients, there was low inter-individual (CV = 21%) and intra-individual variability (CV = 12%) following busulfan exposure.

Distribution

The terminal volume of distribution (Vz) ranges from 0.62 to 0.85 L/kg.

Busulfan concentrations in cerebrospinal fluid are comparable to those in plasma, although they are likely insufficient to induce antitumor activity. Reversible binding of busulfan to plasma proteins is approximately 7%, while irreversible binding, primarily to albumin, is approximately 32%.

Metabolism

Busulfan is primarily metabolized via conjugation with glutathione (spontaneously or catalyzed by glutathione-S-transferase). The glutathione conjugate is then further metabolized in the liver via oxidation. None of the metabolites are believed to significantly contribute to the efficacy or toxicity of busulfan.

Elimination

Total plasma clearance ranges from 2.25 to 2.74 mL/min/kg. The elimination half-life ranges from 2.8 to 3.9 hours.

Approximately 30% of the administered dose is excreted in urine within 48 hours, of which 1% is unchanged. Fecal excretion is minimal. Irreversible binding to plasma proteins may explain incomplete excretion. The role of long-acting metabolites cannot be excluded.

Linearity

After intravenous administration of busulfan at doses up to 1 mg/kg body weight, a dose-proportional increase in busulfan exposure has been demonstrated.

Compared to regimens involving four daily doses, once-daily dosing is characterized by higher peak concentrations, absence of drug accumulation, and a washout period (with no circulating busulfan) between doses. A literature review enabled comparison across multiple pharmacokinetic studies, both within and between trials, and showed consistent, dose-independent pharmacokinetic parameters regardless of dose or dosing schedule. The recommended intravenous dose of busulfan, whether administered as a single infusion (3.2 mg/kg) or divided into four infusions (0.8 mg/kg), likely provides equivalent daily plasma exposure with similar inter- and intra-individual variability.

As a result, therapeutic AUC monitoring of intravenous busulfan remains unchanged, and the therapeutic efficacy of both regimens is comparable.

Pharmacokinetic-Pharmacodynamic Relationships

Literature data suggest that the therapeutic window for busulfan AUC lies between 900 mmol/L·min and 1500 mmol/L·min per dose (corresponding to a daily exposure of 3600 mmol/L·min to 6000 mmol/L·min). In clinical trials with intravenous busulfan at 0.80 mg/kg four times daily, 90% of patient AUCs were below the upper limit of the AUC (1500 mmol/L·min), and at least 80% were within the target therapeutic window (900–1500 mmol/L·min). Similar results are observed with a daily exposure of 3600–6000 mmol/L·min after intravenous administration of busulfan at 3.2 mg/kg body weight once daily.

Special Patient Populations

Hepatic or Renal Impairment

The effect of renal impairment on the disposition of intravenous busulfan has not been studied.

The effect of hepatic impairment on the disposition of intravenous busulfan has not been studied.

However, the risk of hepatotoxicity may be increased in this population.

There are no data on the effect of age on the clearance of intravenous busulfan in patients aged 60 years and older.

Children and Adolescents

Consistent variability in clearance ranging from 2.52 to 3.97 mL/min/kg has been established in children aged <6 months to 17 years. The terminal half-life ranged from 2.24 to 2.5 hours.

Inter- and intra-individual variability in plasma exposure was below 20% and 10%, respectively. A population pharmacokinetic analysis was conducted in a cohort of 205 children with uniform distribution by body weight (3.5 to 62.5 kg), biological characteristics, and underlying conditions (malignant and non-malignant), representative of the broad heterogeneity of children undergoing HSCT. This study demonstrated that body weight is the primary covariate responsible for variability in busulfan pharmacokinetics in children, independent of body surface area or age.

The recommended pediatric dosing allows achievement of concentrations within the therapeutic window (900–1500 mmol/L·min) in more than 70–90% of children with body weight ≥ 9 kg. However, greater variability was observed in children with body weight < 9 kg, resulting in concentrations within the therapeutic window (900–1500 mmol/L·min) in only about 60% of these children. In 40% of children with body weight < 9 kg, AUC values were outside the target range, with values equally distributed below or above the limits (i.e., 20% had AUC <900 mmol/L·min and >1500 mmol/L·min after a 1 mg/kg dose). Therefore, in children with body weight <9 kg, monitoring of busulfan plasma levels (therapeutic drug monitoring) for appropriate dose adjustment may improve achievement of target drug concentrations, especially in very young children and neonates.

Pharmacokinetic-Pharmacodynamic Relationships

Successful engraftment in all patients in phase II studies supports the validity of the accepted AUC targets. The occurrence of veno-occlusive disease (VOD) was not associated with overdosing. A pharmacokinetic-pharmacodynamic relationship has been demonstrated between stomatitis incidence and AUC in patients undergoing autologous transplantation, as well as between bilirubin elevation and AUC in a combined analysis of patients undergoing autologous and allogeneic transplantation.

Clinical characteristics.

Indications.

Busulfan followed by cyclophosphamide (BuCy2) is indicated as conditioning therapy prior to conventional hematopoietic progenitor cell transplantation (HPCT) in adult patients when this combination is considered the best available treatment option.

Busulfan is indicated following fludarabine (FluBu) as conditioning therapy prior to hematopoietic progenitor cell transplantation (HPCT) in adult patients who are candidates for reduced-intensity conditioning (RIC) regimens.

Busulfan followed by cyclophosphamide (BuCy2) or melphalan (BuMel) is indicated as conditioning therapy prior to standard bone marrow progenitor cell transplantation (BMT) in children and adolescents.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Pregnancy.

Interaction with other medicinal products and other forms of interaction.

No specific clinical studies have been conducted to evaluate drug interactions between intravenous busulfan and itraconazole or metronidazole. According to published studies in adults, administration of itraconazole to patients receiving high-dose busulfan may result in decreased busulfan clearance. Cases of increased plasma busulfan levels following metronidazole administration have also been reported. When itraconazole is used for antifungal prophylaxis in combination with intravenous busulfan, patients should be closely monitored for signs of busulfan toxicity.

Published study results in adults indicate that ketobemidone (an analgesic) may increase busulfan plasma concentrations. Therefore, caution should be exercised when these medicinal products are used concomitantly.

Reports during treatment with the BuCy2 regimen in adults have indicated that the interval between the last oral dose of busulfan and the first dose of cyclophosphamide may contribute to the development of toxicity. A reduction in veno-occlusive disease (VOD) and other toxic effects associated with this treatment regimen has been observed in patients in whom the interval between the last oral dose of busulfan and the first dose of cyclophosphamide exceeded 24 hours.

There is no common metabolic pathway between busulfan and fludarabine.

Published studies in adults using the FluBu regimen have shown no interaction between intravenous busulfan and fludarabine.

In children and adolescents receiving the BuMel regimen, administration of melphalan less than 24 hours after the last oral dose of busulfan has been found to cause toxicity.

Paracetamol reduces glutathione levels in blood and tissues and may therefore lead to decreased busulfan clearance when used in combination therapy (see section "Special precautions for use").

In clinical trials of intravenous busulfan, patients were administered phenytoin or benzodiazepines for seizure prophylaxis (see sections "Dosage and administration" and "Special precautions for use"). Concomitant use of phenytoin in patients receiving high oral doses of busulfan increased busulfan clearance due to induction of glutathione-S-transferase. No interactions were observed with benzodiazepines such as diazepam, clonazepam, and lorazepam when used for seizure prophylaxis during high-dose busulfan therapy.

Data on busulfan do not show any evidence of an inductive effect by phenytoin. A phase II clinical trial was conducted to evaluate the impact of prophylactic anticonvulsant therapy on the pharmacokinetics of intravenous busulfan. In this study, 24 adult patients received clonazepam (0.025–0.03 mg/kg body weight/day by continuous intravenous infusion) as anticonvulsant prophylaxis. Pharmacokinetic data from these patients were compared with historical data from patients who received phenytoin. Population pharmacokinetic analysis showed no differences in intravenous busulfan clearance between patients treated with phenytoin and those treated with clonazepam, indicating that similar busulfan plasma concentrations were achieved regardless of the type of anticonvulsant prophylaxis used.

No interactions were observed when busulfan was administered concomitantly with fluconazole (an antifungal agent) or with 5-HT3 receptor antagonists used as antiemetics, such as ondansetron and granisetron.

Enhanced effects of busulfan have been observed when administered concomitantly with deferasirox. The mechanism underlying this interaction is not fully understood. Regular monitoring of busulfan plasma concentrations is recommended, and dose adjustment of busulfan may be necessary in patients who are currently or recently receiving deferasirox.

Special precautions for use.

Treatment with busulfan at the recommended dose and regimen leads to pronounced myelosuppression in all patients. Severe granulocytopenia, thrombocytopenia, anemia, or any combination thereof may occur. During treatment and until recovery, complete blood counts, including leukocyte and platelet counts, should be performed frequently.

Prophylactic or empirical use of anti-infective agents (antibacterial, antifungal, antiviral) should be considered to prevent and treat infections associated with neutropenia. Depending on clinical indications, platelet and red blood cell transfusions, as well as growth factors such as granulocyte colony-stimulating factor (G-CSF), may be used.

In adult patients, the total neutrophil count on average was <0.5 x 10⁹/L in 100% of patients by day 4 after transplantation and normalized on average by day 10 and day 13 after autologous and allogeneic transplantation, respectively (mean duration of neutropenia was 6 and 9 days, respectively). Thrombocytopenia (<25 x 10⁹/L or requiring platelet transfusion) occurred on average by day 5–6 in 98% of patients. Anemia (hemoglobin <8.0 g/dL) occurred in 69% of patients.

In children and adolescents, the absolute neutrophil count on average was <0.5 x 10⁹/L in 100% of patients by day 3 after transplantation and normalized on average by day 5 and day 18.5 after autologous and allogeneic transplantation, respectively. In children, thrombocytopenia (<25 x 10⁹/L or requiring platelet transfusion) occurred in 100% of patients. Anemia (hemoglobin <8.0 g/dL) occurred in 100% of patients.

In children with body weight <9 kg, therapeutic drug monitoring may be required in individual cases, especially in very young children and neonates (see section "Pharmacokinetics").

Fanconi anemia cells are hypersensitive to cross-linking agents.

Clinical experience with busulfan as conditioning therapy prior to bone marrow transplantation in children with Fanconi anemia is limited. Therefore, the medicinal product Busulfan Accord should be used with caution in this patient group.

Hepatic dysfunction

The use of busulfan in patients with impaired liver function has not been studied. Since busulfan is primarily metabolized in the liver, caution should be exercised when administering it to patients with pre-existing hepatic impairment, particularly severe liver dysfunction. To enable early diagnosis of hepatotoxicity, serum activities of aminotransferases, alkaline phosphatase, and bilirubin should be measured regularly during the 28 days following transplantation.

Veno-occlusive liver disease (VOD) is a serious complication that may occur during treatment with Busulfan Accord. Patients who have previously received radiation therapy, three or more courses of chemotherapy, or prior stem cell transplantation may have an increased risk of developing VOD (see section "Undesirable effects").

Paracetamol should be used with caution before (less than 72 hours) or during treatment with Busulfan Accord, as busulfan metabolism may be slowed (see section "Interaction with other medicinal products and other forms of interaction").

In clinical studies, cardiac tamponade or other specific cardiotoxicity related to busulfan has not been observed. However, cardiac function should be monitored regularly in patients receiving busulfan (see section "Undesirable effects").

In studies with busulfan, one fatal case of acute respiratory distress syndrome with subsequent respiratory failure associated with interstitial lung fibrosis has been reported, although the etiology of this syndrome remains unclear. In addition, busulfan may cause pulmonary toxicity, which may potentiate the effects of other cytotoxic agents. Therefore, any respiratory symptoms in patients who have previously received mediastinal or lung irradiation should be carefully monitored (see section "Undesirable effects").

During treatment with Busulfan Accord, periodic monitoring of renal function should be considered (see section "Undesirable effects").

Seizures have been reported during administration of high-dose busulfan. Particular caution should be exercised when administering the recommended doses of Busulfan Accord to patients with a history of seizures. Appropriate anticonvulsant prophylaxis should be administered. In adults and children, all available study data on seizure prophylaxis during busulfan treatment refer to phenytoin or benzodiazepines. The effect of these anticonvulsants on the pharmacokinetics of busulfan has been evaluated in phase II studies (see section "Interaction with other medicinal products and other forms of interaction").

Patients should be informed about the increased risk of developing secondary neoplastic disease. Based on human studies, busulfan has been classified by the International Agency for Research on Cancer (IARC) as a human carcinogen. The World Health Organization (WHO) has recognized a causal relationship between busulfan exposure and cancer. Multiple cytogenetic abnormalities have been observed in patients with leukemia treated with busulfan, and some have developed secondary malignancies. Busulfan is considered leukemogenic.

Fertility

Busulfan may reduce fertility. Therefore, men treated with Busulfan Accord are advised not to plan fatherhood during treatment and for 6 months after treatment, and should consider sperm cryopreservation prior to starting therapy due to the risk of irreversible infertility resulting from treatment with Busulfan Accord. Ovarian function suppression, amenorrhea, and menopause frequently occur in premenopausal women. Treatment with busulfan in girls of prepubertal age delayed maturation due to ovarian insufficiency. Male impotence, infertility, sperm loss, and testicular atrophy have been reported. The excipient dimethylacetamide (DMA) may also impair fertility. DMA reduces fertility in male and female rodents (see section "Use during pregnancy or breastfeeding").

Use during pregnancy or breastfeeding.

Pregnancy

HSCT is contraindicated in pregnant women; therefore, the use of Busulfan Accord during pregnancy is contraindicated. Animal studies have shown reproductive toxicity (embryo- and fetotoxicity, and teratogenic effects) (see section "Pharmacokinetics").

There are no or limited data on the use of busulfan and DMA in pregnant women. Several cases of congenital anomalies have been reported following oral administration of low doses of busulfan, but a causal relationship with the active substance has not been established. It has also been concluded that exposure during the third trimester of pregnancy may lead to impaired fetal intrauterine development.

Women of childbearing potential

Women of childbearing potential must use effective contraception during treatment and for 6 months after discontinuation of treatment.

Breastfeeding

It is unknown whether busulfan and DMA are excreted in human breast milk. Due to the confirmed carcinogenic potential of busulfan in human and animal studies, breastfeeding must be discontinued during treatment with busulfan.

Fertility

Busulfan and DMA may impair male and female fertility. For this reason, men are advised to use measures to prevent conception during treatment and for a period of 6 months after completion of treatment, and to consider sperm cryopreservation prior to starting treatment due to the possibility of irreversible infertility (see section "Special precautions for use").

Ability to affect reaction speed when driving vehicles or operating machinery.

Do not use.

Method of Administration and Dosage

The medicinal product Busulfan Accord must be administered under the supervision of a physician experienced in conditioning therapy prior to hematopoietic progenitor cell transplantation.

Busulfan Accord is indicated prior to hematopoietic progenitor cell transplantation (HPCT).

Dosage

Busulfan Accord in combination with cyclophosphamide or melphalan

Adults

Recommended dosage and administration schedule:

• 0.8 mg/kg body weight of busulfan as a two-hour infusion every 6 hours for 4 consecutive days, for a total of 16 doses;
• followed by cyclophosphamide at a dose of 60 mg/kg body weight/day for 2 days, starting no earlier than 24 hours after the 16th dose of Busulfan Accord (see section "Interaction with other medicinal products and other forms of interaction").

Children and adolescents (from 0 to 17 years of age)

The recommended dose of Busulfan Accord is:

Next:

• cyclophosphamide in 4 cycles at a dose of 50 mg/kg body weight (BuCy4) or
• single-dose melphalan 140 mg/m² body surface area (BuMel);

starting administration no sooner than 24 hours after the 16th dose of Busilvex (see section "Interaction with other medicinal products and other forms of interaction").

Busilvex should be administered over 2 hours every 6 hours for 4 consecutive days, for a total of 16 doses, prior to administration of cyclophosphamide or melphalan and haematopoietic progenitor cell transplantation (HPCT).

Elderly patients

In patients aged 50 years and older (n = 23), treatment with Busilvex was successful without dose adjustment. However, there is limited information on the safety of Busilvex in patients aged 60 years and older.

Elderly patients should receive the same doses as adult patients (< 50 years) (see section "Pharmacokinetics").

Busilvex in combination with Fludarabine (FB)

Adults

Recommended dose and regimen:

• Fludarabine should be administered as a single daily 1-hour infusion of 30 mg/m² for 5 consecutive days, or 40 mg/m² body surface area for 4 consecutive days.
• Busilvex should be administered at a dose of 3.2 mg/kg body weight as a single 3-hour infusion immediately after fludarabine for 2 or 3 consecutive days.

Children and adolescents (from 0 to 17 years)

The safety and efficacy of FB in children and adolescents have not been established.

Elderly patients

The use of the FB regimen in elderly patients has not been studied. However, publications have reported over 500 patients aged ≥ 55 years who received the FB conditioning regimen, and the efficacy results were similar to those in younger patients. Dose adjustment was not required.

Patients with obesity

Adults

In obese patients, dosing based on adjusted body mass index (ABMI) should be considered.

Body mass index (BMI) is calculated as follows:

BMI for men (kg) = 50 + 0.91 × (height in cm – 152);
BMI for women (kg) = 45 + 0.91 × (height in cm – 152).

Adjusted body mass index (ABMI) is calculated as follows:

ABMI = BMI + 0.25 × (actual body weight – BMI)

Children and adolescents

This medicinal product is not recommended for use in children and adolescents with obesity, defined as body mass index: weight (kg)/(body surface area in m²) > 30 kg/m², until additional data become available.

Patients with renal impairment

Studies in patients with renal impairment have not been conducted. However, since busulfan is moderately excreted in urine, dose adjustment in these patients is not recommended.

Nevertheless, caution is advised when administering the drug (see section "Side effects" and section "Pharmacokinetics").

Patients with hepatic impairment

The use of busulfan in patients with hepatic impairment has not been studied.

Caution is recommended, especially in patients with severe hepatic impairment (see section "Special precautions for use").

Method of administration

Precautions to be taken before administration or infusion of the medicinal product

Busilvex must be diluted before administration. The final concentration of busulfan should be approximately 0.5 mg/mL. The medicinal product Busilvex should be administered intravenously via a central catheter.

Instructions for dilution of the medicinal product before administration

Preparation of the medicinal product Busilvex

Proper procedures for preparation and disposal of cytotoxic medicinal products must be followed.

All preparation procedures require strict adherence to aseptic techniques, preferably using a vertical laminar airflow cabinet.

As with other cytotoxic compounds, caution should be exercised when preparing and administering busulfan:

• gloves and protective clothing are recommended,
• in case of contact of the concentrate or diluted solution of busulfan with skin or mucous membranes, the affected area should be immediately and thoroughly rinsed with water.

Calculation of the amount of medicinal product Busilvex to be diluted and the volume of diluent

Prior to administration, the medicinal product Busilvex must be diluted with 0.9% sodium chloride solution (9 mg/mL) for injection or 5% glucose solution for injection.

The volume of diluent should be 10 times the volume of the medicinal product Busilvex to achieve a final busulfan concentration of approximately 0.5 mg/mL. For example:

The amount of medicinal product Busilvex and diluent should be calculated as follows:

for a patient with body weight Y kg:

• Amount of medicinal product Busilvex:

Y: patient's body weight in kg

D: dose of busulfan

• Volume of diluent:

(A (ml of Busulfan Accord medicinal product)) x (10) = B (ml of diluent)

To prepare the final infusion solution, add (A) ml of the medicinal product Busulfan Accord to (B) ml of diluent (0.9% sodium chloride injection solution [9 mg/ml] or 5% glucose injection solution).

Preparation of infusion solution

• Busulfan Accord must be prepared by healthcare professionals using sterile equipment. Using a non-polycarbonate syringe with a needle:
  • withdraw the calculated volume of the medicinal product Busulfan Accord from the vial;
  • inject the contents of the syringe into an infusion bag (or syringe) already containing the calculated volume of the selected diluent. The medicinal product Busulfan Accord should always be added to the diluent, not the diluent to the medicinal product. Busulfan Accord must not be added to an infusion bag that does not contain 0.9% (9 mg/ml) sodium chloride injection solution or 5% glucose injection solution.
• The diluted solution must be thoroughly mixed by inverting several times.

After dilution, each ml of the infusion solution contains 0.5 mg of busulfan.

After dilution, the medicinal product Busulfan Accord should be a clear, colourless solution.

Instructions for use

The central venous catheter should be flushed with approximately 5 ml of 0.9% (9 mg/ml) sodium chloride injection solution or 5% glucose injection solution before and after each infusion.

Residual drug remaining in the tubing should not be flushed through, as rapid infusion of busulfan has not been studied and is not recommended.

The entire prescribed dose of the medicinal product Busulfan Accord should be administered over two or three hours, depending on the conditioning regimen.

Small volumes may be administered over 2 hours using an electric syringe pump. In this case, infusion sets with minimal priming volume (e.g., 0.3–0.6 ml) should be used. The infusion set should be pre-filled with the drug solution prior to the start of actual infusion, then flushed with 0.9% sodium chloride injection solution (9 mg/ml) or 5% glucose injection solution.

Busulfan Accord must not be administered simultaneously with other intravenous solutions.

Polycarbonate syringes must not be used for administration of the medicinal product Busulfan Accord.

For single use only. Use only clear solution, free from cloudiness.

Diluted solution

Chemical and physical stability after dilution with 5% glucose solution or 0.9% sodium chloride injection solution (9 mg/ml) has been confirmed for the following periods:

• up to 4 hours (including infusion time) after dilution when stored at 20 °C – 25 °C,
• up to 15 hours after dilution when stored at 2 °C – 8 °C, followed by up to 3 hours at 20 °C – 25 °C (including infusion time).

From a microbiological standpoint, the product should be used immediately. If not used immediately, the responsibility for storage conditions and duration prior to use lies with the user.

Any unused medicinal product or waste material derived from it should be disposed of in accordance with local regulations for cytotoxic agents.

Busulfan Accord must not be administered as an intravenous bolus injection or by injection into peripheral veins.

Each patient should receive prophylactic anticonvulsant medication to prevent seizures, which have been reported with high-dose busulfan.

Anticonvulsant agents are recommended to be administered starting 12 hours before the first dose and continuing until 24 hours after the last dose of Busulfan Accord.

In clinical studies in adults, as well as in children and adolescents, patients received phenytoin or benzodiazepines for seizure prophylaxis (see section "Special precautions for use" and section "Interaction with other medicinal products and other forms of interaction").

Anticonvulsant agents should be administered prior to the first dose of Busulfan Accord, and this treatment should be continued according to standard local recommendations throughout the entire treatment period.

Overdose

The main toxic effects are bone marrow ablation and severe pancytopenia; however, disorders of the central nervous system (CNS), liver, lungs, and gastrointestinal tract may also occur.

There is no known antidote for busulfan except hematopoietic progenitor cell transplantation (HPCT). In the absence of HPCT, the recommended dose of Busulfan Accord may lead to busulfan overdose. The patient's hematological status should be closely monitored and intensive supportive therapy should be provided as directed by the physician.

In two reported cases, busulfan was shown to be dialyzable, and therefore dialysis should be considered in cases of overdose. Since busulfan is metabolized via conjugation with glutathione, administration of glutathione may be considered.

It should be remembered that overdose of Busulfan Accord also leads to increased exposure to DMA. In humans, the main toxic effects include hepatotoxicity and effects on the CNS. CNS changes precede the onset of other, more serious adverse effects. There is no known specific antidote for DMA. In case of overdose, treatment includes general supportive measures.

Adverse Reactions

Summary of Drug Safety Study Results

Busulfan in Combination with Cyclophosphamide or Melphalan

Adults

Data on adverse reactions are based on two clinical studies (n = 103) using busulfan.

Severe cardiovascular, hepatic, and respiratory toxicity were considered expected consequences of the conditioning (ablative) regimen and the transplantation process. Infections and graft-versus-host reaction (GVHD), although not directly related, were the most significant causes of morbidity and mortality, particularly following allogeneic HSCT.

Blood and Lymphatic System Disorders

Myelosuppression and immunosuppression are desired therapeutic effects within conditioning therapy. Thus, significant cytopenia was observed in all patients: leukopenia in 96%, thrombocytopenia in 94%, and anemia in 88%. The median time to onset of neutropenia was 4 days in both autologous and allogeneic transplant patients. The median duration of neutropenia was 6 days for autologous and 9 days for allogeneic transplants, respectively.

Immune System Disorders

Data on the incidence of acute graft-versus-host disease (aGVHD) were obtained from study OMC-BUS-4 (allogeneic transplants) (n = 61). aGVHD was observed in 11 patients (18%). The incidence of grade III aGVHD was 13% (8/61), and grade III–IV aGVHD was 5% (3/61). Acute GVHD was considered severe in 3 patients. Chronic GVHD (cGVHD) was reported only if it was severe or fatal (3 cases resulted in fatal outcomes).

Infections and Parasitic Infections

One or more episodes of infection occurred in 39% of patients (40/103), of which 83% (33/40) were classified as mild or moderate. Pneumonia resulted in fatal outcomes in 1% (1/103) and was considered life-threatening in 3% of patients. Other infections were considered severe in 3% of patients. Fever was recorded in 87% of patients, with 84% classified as mild/moderate and 3% as severe. Chills were recorded in 47% of patients, being mild/moderate in 46% and severe in 1%.

Hepatobiliary Disorders

Hepatotoxic reactions accounted for 15% of severe adverse reactions.

Veno-occlusive disease (VOD) is considered a potential complication of conditioning therapy following transplantation. VOD was observed in 6 out of 103 patients (6%). VOD occurred in 8.2% (5/61) of allograft recipients (with fatal outcomes in 2 patients) and in 2.5% (1/42) of autologous transplant recipients. Elevated bilirubin (n = 3) and aspartate aminotransferase (AST) (n = 1) were also observed. Two out of the four above-mentioned patients with signs of hepatotoxicity belonged to the group diagnosed with VOD.

Respiratory, Thoracic and Mediastinal Disorders

In studies using busulfan, acute respiratory distress syndrome with subsequent fatal respiratory failure during interstitial pulmonary fibrosis was observed in one patient.

Children and Adolescents

Information on adverse reactions was obtained from a clinical study in children and adolescents (n = 55). Severe toxic reactions affecting the liver and respiratory system were considered expected outcomes of conditioning therapy and the transplantation process.

Immune System Disorders

Data on the incidence of acute graft-versus-host disease (aGVHD) were obtained from allograft recipients (n = 28). aGVHD developed in 14 patients (50%). The incidence of grade I–II aGVHD was 46.4% (13/28), and grade III–IV aGVHD was 3.6% (1/28). Chronic GVHD (cGVHD) was reported only when it led to a fatal outcome: one patient died 13 months after transplantation.

Infections and Parasitic Infections

Infections (documented and undocumented neutropenic fever) occurred in 89% of patients (49/55). Mild/moderate fever was observed in 76% of patients.

Hepatobiliary Disorders

Grade 3 elevation of transaminases was detected in 24% of patients.

Hepatic veno-occlusive disease (VOD) was reported in 15% (4/27) and 7% (2/28) of autologous and allogeneic transplants, respectively. VOD did not result in fatal outcomes, was not severe, and resolved in all cases.

Busulfan in Combination with FB

Adults

The safety profile of busulfan in combination with FB was evaluated based on a review of adverse reactions from published clinical trial data using reduced-intensity conditioning (RIC) regimens. In these studies, a total of 1574 patients received FB as reduced-intensity conditioning therapy prior to hematopoietic progenitor cell transplantation.

Myelosuppression and immunosuppression were intended therapeutic effects of conditioning therapy and therefore were not considered adverse effects.

Infections and Parasitic Infections

The presence of infections or reactivation of opportunistic infectious agents reflects the immune status of patients undergoing conditioning therapy.

The most commonly reported infectious adverse effects included: cytomegalovirus reactivation [range: 30.7–80.0%], Epstein-Barr virus reactivation [range: 2.3–61%], bacterial infections [range: 32.0–38.9%], and viral infections [range: 1.3–17.2%].

Gastrointestinal Disorders

The highest frequency of nausea and vomiting was 59.1%, and the highest frequency of stomatitis was 11%.

Renal and Urinary Disorders

Conditioning regimens containing fludarabine were presumed to be associated with a higher incidence of post-transplant opportunistic infections due to the immunosuppressive effect of fludarabine. Late hemorrhagic cystitis occurring 2 weeks after transplantation may be related to viral infection or reactivation. Hemorrhagic cystitis, including cases caused by viral infection, was reported in the range of 16% to 18.1%.

Hepatobiliary Disorders

Hepatic veno-occlusive disease (VOD) was reported in the range of 3.9% to 15.4%.

Treatment-related mortality/non-relapse mortality (TRM/NRM) reported within 100 days post-transplantation was also analyzed based on a review of published clinical trial data. Fatal outcomes were considered related to secondary adverse events following GVHD and were not associated with relapse/progression of hematologic malignancies.

The most common causes of TRM/NRM were infection/sepsis, GVHD, lung disease, and organ failure.

List of Adverse Reactions

Adverse reactions reported as isolated cases are listed below by system organ class and frequency: very common (≥1/10), common (≥1/100 to <1/10), rare (≥1/1000 to <1/100), frequency not known (cannot be estimated from available data).

The frequency of adverse reactions reported after drug marketing authorization is listed under the "frequency not known" category in the tables below.

Busulfan in Combination with Cyclophosphamide or Melphalan

Adverse reactions reported in more than isolated cases in adults and children are listed below by system organ class and frequency of occurrence. Within each frequency group, adverse reactions are presented in order of decreasing frequency.

Adverse reactions are listed in decreasing order of severity within each frequency category.

* hepatic veno-occlusive disease occurs more frequently in children and adolescents

** reported post-marketing with intravenous busulfan

*** reported post-marketing with oral busulfan

Busulfan in combination with Fludarabine

The frequency of individual adverse reactions listed in the table below is determined according to the highest incidence observed in published clinical trials using RIC regimens, with a clearly defined patient population receiving fludarabine, regardless of busulfan dosing regimens and endpoints. Adverse reactions reported in more than isolated cases in adults and children are listed below by system organ class and frequency of occurrence.

* reported in the post-marketing period

** including hemorrhagic cystitis caused by viral infection

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after the medicinal product has been authorized is important. This allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions to the Department of Monitoring of Adverse Drug Reactions, Division of Registration of Medicinal Products, Medical Devices and Biocidal Products

Al. Jerozolimskich 181C

02-222 Warsaw

Tel.: + 48 22 49 21 301

Fax: + 48 22 49 21 309

Website: https://smz.ezdrowie.gov.pl

Adverse reactions can also be reported to the marketing authorization holder.

Shelf life.

18 months.

Storage conditions.

Store in a refrigerator at a temperature of 2 °C to 8 °C.

Do not freeze the diluted solution.

Keep out of the reach of children.

Incompatibilities.

Due to lack of compatibility studies, busulfan must not be mixed with other medicinal products except those specified in the section "Instructions for use and handling" and "Dosage and method of administration".

Do not use polycarbonate syringes for administration of Busulfan Accord.

Packaging.

10 ml in a vial, 1 vial in a carton.

Prescription status.

Prescription only.

Manufacturer.

Accord Healthcare Polska Sp. z o.o. Importer's formulation / Accord Healthcare Polska Sp. z o.o. Importer's warehouse.

Manufacturer's address and place of business.

ul. Lutomierska 50, Pabianice, 95-200, Poland / ul. Lutomierska 50, Pabianice, 95-200, Poland.

Marketing authorization holder.

Accord Healthcare Polska Sp. z o.o. / Accord Healthcare Polska Sp. z o.o.

Address of the marketing authorization holder.

7 Tasmowa St., Warsaw, 02-677, Poland / 7 Tasmowa St., Warsaw, 02-677, Poland.