Busulfan mili

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BUSULFAN MILI (BUSULFANMILI)

Composition:

Active substance: busulfan;

1 ml of concentrate contains: 6 mg of busulfan (60 mg/10 ml);

after dilution: 1 ml of solution contains 0.5 mg of busulfan;

Excipients: dimethylacetamide, polyethylene glycol 400.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colorless solution.

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 effect of the drug.

Clinical Efficacy and Safety

Busulfan in Combination with Cyclophosphamide

Adults. Data on the safety and efficacy of busulfan in combination with cyclophosphamide administered over 2 days (BuCy2 regimen) prior to standard allogeneic and/or autologous hematopoietic progenitor cell transplantation (HPCT) were obtained from two clinical studies (OMC-BUS-4 and OMC-BUS-3).

Two prospective, open-label, non-comparative Phase II studies were conducted in patients with hematological disorders, mostly at advanced stages.

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 accelerated phase; primary refractory or relapsed Hodgkin’s disease or non-Hodgkin’s lymphoma; and myelodysplastic syndrome.

Patients received busulfan at 0.8 mg/kg body weight as an infusion every 6 hours for a total of 16 doses, followed by cyclophosphamide at 60 mg/kg body weight once daily for 2 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 No patient was withdrawn from the study due to adverse effects related to busulfan.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 × 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. Overall mortality from any cause and non-relapse mortality beyond 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. Data on the safety and efficacy of busulfan in combination with cyclophosphamide administered over 4 days (BuCy4 regimen) or melphalan (BuMel regimen) prior to standard allogeneic and/or autologous HPCT were obtained from the clinical study F60002 IN 101 G0.

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

All patients experienced profound bone marrow suppression. The time to achieve an absolute neutrophil count (ANC) > 0.5 × 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

Adults. Data on the safety and efficacy of busulfan in combination with fludarabine (FB) prior to allogeneic HPCT were derived from published results of 7 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 consisting of fludarabine followed by a single daily dose of intravenous busulfan at 3.2 mg/kg for 2 or 3 consecutive days. The total cumulative dose of busulfan per patient ranged from 6.4 mg/kg to 9.6 mg/kg. The combination with fludarabine provided adequate myeloablation, the intensity of which was modulated by adjusting 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 adverse effects.

Data from a recently completed multicenter, prospective Phase II study involving 80 patients aged 18 to 65 years with various hematological malignancies who received fludarabine and a 3-day course of busulfan prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) demonstrated the feasibility of reduced-intensity conditioning. In this study, all but one patient received the graft, with a median time to engraftment of 15 days (range: 10–23 days) after allo-HSCT. The cumulative incidence of neutrophil recovery by day 28 was 98.8% (95% CI [confidence interval]: 85.7–99.9). Platelet engraftment occurred at a median of 9 days (range: 1–16 days) after allo-HSCT.

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

Pharmacokinetics

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

Adults

Absorption. The pharmacokinetics of intravenous busulfan were studied in 124 patients after a two-hour intravenous infusion — a total of 16 doses over 4 days. After intravenous infusion, the bioavailability of the busulfan dose is immediate and complete. Plasma concentrations of busulfan in adult patients receiving the drug orally (1 mg/kg body weight) and intravenously (0.8 mg/kg body weight) were similar. In a population pharmacokinetic analysis conducted in 102 patients, there was low inter-subject (CV [coefficient of variation] = 21%) and intra-subject variability (CV = 12%) following busulfan administration.

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

Busulfan concentrations in cerebrospinal fluid are comparable to plasma concentrations, but are likely insufficient to provide antitumor activity. Reversible plasma protein binding 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. It is believed that none of the metabolites 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. Incomplete excretion may be due to irreversible binding to plasma proteins. The role of long-acting metabolites cannot be excluded.

Linearity. Following 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 administration results in higher peak concentrations, absence of drug accumulation, and a washout phase (when busulfan is not circulating in plasma) between doses. Comparison of pharmacokinetic data, both within and across studies, showed that the pharmacokinetic parameters of busulfan remain unchanged regardless of dose or dosing regimen. 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 comparable plasma concentrations with similar inter- and intra-subject variability.

As a result, the AUC of intravenous busulfan within the therapeutic window remains unchanged, and the therapeutic efficacy of both regimens is similar.

Pharmacokinetic-Pharmacodynamic Relationships. According to scientific publications, the therapeutic window for busulfan AUC is 900–1500 mmol/L·min per dose (corresponding to daily exposure of 3600–6000 mmol/L·min). In clinical trials with intravenous busulfan at 0.80 mg/kg administered four times daily, AUC values in 90% of patients were below the upper limit (1500 mmol/L·min), and in at least 80% of patients were within the target therapeutic window (900–1500 mmol/L·min). With once-daily intravenous administration of busulfan at 3.2 mg/kg body weight, a similar level of daily exposure (3600–6000 mmol/L·min) is achieved.

Special Patient Groups

Hepatic or Renal Impairment. The effect of renal or hepatic impairment on the pharmacokinetics of intravenous busulfan has not been studied.

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

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

Children

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

Inter-subject variability in plasma exposure was less than 20%, and intra-subject variability was less than 10%. A population pharmacokinetic analysis was conducted in a cohort of 205 children with a uniform distribution of body weight (3.5–62.5 kg), biological characteristics, and underlying diseases (malignant and non-malignant), ensuring representativeness of the heterogeneous patient group undergoing HPCT. In this study, body weight was identified as the main covariate influencing the variability of busulfan pharmacokinetics in children, while body surface area or age had no significant impact.

The recommended dosing for children achieved concentrations within the therapeutic window (900–1500 mmol/L·min) in more than 70–90% of patients with body weight ≥9 kg. However, in children with body weight <9 kg, significant variability was observed, resulting in therapeutic window concentrations (900–1500 mmol/L·min) being achieved in only approximately 60% of cases. In 40% of children with body weight <9 kg, concentrations fell outside the target range, with AUC values evenly distributed: in 20% of patients AUC was <900 mmol/L·min, and in 20% AUC was >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) and dose adjustment are recommended to achieve target drug concentrations, especially in very young children and neonates.

Pharmacokinetic-Pharmacodynamic Relationships. Successful engraftment in all patients in Phase II studies confirms the validity of the accepted AUC values. A relationship between pharmacokinetics and pharmacodynamics has been demonstrated through correlations between stomatitis incidence and AUC values in autologous transplant patients, and between increased bilirubin levels and AUC in both autologous and allogeneic transplant recipients. The occurrence of veno-occlusive disease was not associated with overdosing.

Clinical Characteristics

Indications

The use of the medicinal product Busulfan Mili 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.

The use of the medicinal product Busulfan Mili after administration of fludarabine is indicated as conditioning therapy prior to hematopoietic progenitor cell transplantation (HPCT) in adult patients who are candidates for reduced-intensity conditioning (RIC) regimens.

The use of the medicinal product Busulfan Mili followed by cyclophosphamide (BuCy2) or in combination with melphalan (BuMel) is indicated as conditioning therapy prior to standard bone marrow progenitor cell transplantation (BMT) in children.

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 evaluating the drug interaction between intravenous busulfan and itraconazole have been conducted. According to published data from studies in adults, administration of itraconazole to patients receiving high-dose busulfan may lead to decreased busulfan clearance. Cases of increased plasma busulfan levels after administration of metronidazole have also been reported. When itraconazole is used for antifungal prophylaxis in combination with intravenous busulfan, patients should be monitored closely 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 indicate that during treatment with the BuCy2 regimen in adults, an interval between the last oral dose of busulfan and the first dose of cyclophosphamide may lead to development of toxicity. Reduced severity of veno-occlusive liver disease 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.

Busulfan and fludarabine do not share a common metabolic pathway.

Studies in adults using the FlBu regimen did not reveal any interaction between intravenous busulfan and fludarabine.

In children 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 administration of phenytoin to 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 provide evidence of an inductive effect of 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 therapy. Pharmacokinetic data from these patients were compared with historical data from patients who received phenytoin. Population pharmacokinetic analysis of the data revealed no differences in intravenous busulfan clearance during treatment with phenytoin versus clonazepam; thus, busulfan plasma concentrations were similar regardless of the type of anticonvulsant prophylactic therapy used.

No interactions occurred when busulfan was administered concomitantly with 5-HT3-acting antiemetics such as ondansetron and granisetron.

Increased effects of busulfan have been observed when administered concomitantly with deferasirox. The mechanism underlying this interaction is not fully understood. In patients receiving or who have recently received deferasirox, regular monitoring of plasma busulfan concentrations is recommended, and the busulfan dose should be adjusted as necessary.

Special precautions for use

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

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 administered.

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

In children, the absolute neutrophil count on average fell below 0.5 × 10⁹/L in 100% of patients 3 days after transplantation and normalized on average 5 and 18.5 days after autologous and allogeneic transplantation, respectively. Thrombocytopenia (< 25 × 10⁹/L or requiring platelet transfusion) occurred in 100% of pediatric patients. Anemia (hemoglobin <8.0 g/dL) occurred in 100% of patients.

Therapeutic drug monitoring may be required in children weighing <9 kg, 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, Busulfan Mili 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, it should be administered cautiously to patients with pre-existing hepatic impairment, especially severe hepatic dysfunction. To enable early diagnosis of hepatotoxicity, serum aminotransferase, alkaline phosphatase, and bilirubin levels should be monitored regularly for 28 days after transplantation.

Hepatic veno-occlusive disease (VOD) is a serious complication that may occur during treatment with Busulfan Mili. Patients who have previously received radiation therapy, three or more chemotherapy regimens, or stem cell transplantation are at increased risk of VOD (see section "Adverse reactions").

Paracetamol should be used with caution within 72 hours before or during treatment with Busulfan Mili, as it may slow the metabolism of busulfan (see section "Interaction with other medicinal products and other forms of interaction").

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

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

Periodic monitoring of renal function should be considered during treatment with Busulfan Mili (see section "Adverse reactions").

Seizures have been reported during high-dose busulfan therapy. Particular caution is required when administering the recommended doses of Busulfan Mili to patients with a history of seizures. Appropriate anticonvulsant prophylaxis should be prescribed. All available data on seizure prophylaxis during busulfan therapy in adults and children pertain 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 secondary neoplastic disease. The International Agency for Research on Cancer (IARC), based on human data, has classified busulfan as a human carcinogen. The World Health Organization (WHO) recognizes a causal relationship between busulfan exposure and cancer. Numerous cytogenetic abnormalities have been observed in patients with leukemia treated with busulfan, and some have developed secondary cancers. Busulfan is considered leukemogenic.

Fertility

Busulfan may reduce fertility.

Men receiving Busulfan Mili are advised not to plan fatherhood during treatment and for 6 months after its completion. Cryopreservation of sperm should also be considered prior to starting therapy due to the risk of irreversible infertility caused by busulfan treatment.

In premenopausal women receiving busulfan, ovarian function suppression, amenorrhea, and menopause frequently occur. In prepubertal girls, busulfan treatment may delay maturation due to ovarian insufficiency. Male impotence, infertility, sperm loss, and testicular atrophy have also been reported.

The excipient dimethylacetamide may also impair fertility. Dimethylacetamide is known to reduce fertility in male and female rodents (see section "Pregnancy or breastfeeding").

Use during pregnancy or breastfeeding

Pregnancy

HSCT is contraindicated in pregnant women; therefore, the use of Busulfan Mili 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 dimethylacetamide in pregnant women. A few 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 development.

Women of reproductive potential

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

Breastfeeding

It is unknown whether busulfan and dimethylacetamide are excreted in breast milk. Given the carcinogenic potential of busulfan demonstrated in animal studies and clinical data in humans, breastfeeding must be discontinued during busulfan treatment.

Fertility

Busulfan and dimethylacetamide may impair male and female fertility. For this reason, men are advised to use contraception during treatment and for 6 months after completion of therapy, and to consider sperm cryopreservation prior to starting treatment due to the potential for irreversible infertility (see section "Special precautions for use").

Ability to affect the speed of reactions while driving or operating machinery

Do not use.

Method of Administration and Dosage

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

Busulfan Mylan is indicated for use prior to hematopoietic progenitor cell transplantation (HPCT).

Dosage

Busulfan Mylan in combination with cyclophosphamide or melphalan

Adults

Recommended dose 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 60 mg/kg body weight/day for 2 days, starting no earlier than 24 hours after the 16th dose of Busulfan Mylan (see section "Interaction with other medicinal products and other forms of interaction").

Children (from 0 to 17 years of age)

Recommended dose of Busulfan Mylan:

Actual body weight (kg)	Busilfex Milli — dose in mg/kg
< 9	1.0
From 9 to < 16	1.2
From 16 to 23	1.1
From > 23 to 34	0.95
> 34	0.8

Next:

• cyclophosphamide in 4 cycles at a dose of 50 mg/kg body weight

or

• single dose of melphalan 140 mg/m² body surface area,

initiated no earlier than 24 hours after the 16th dose of Busulfan Mylan (see section "Interaction with other medicinal products and other forms of interaction").

Busulfan Mylan should be administered as a 2-hour infusion every 6 hours for 4 consecutive days — a total of 16 doses — prior to administration of cyclophosphamide or melphalan and hematopoietic progenitor cell transplantation (HPCT).

Elderly patients

In patients aged 50 years and older (n = 23), therapy with Busulfan Mylan was successful without dose adjustment. However, there is only limited safety information available regarding the use of Busulfan Mylan in patients aged 60 years and older.

Patients aged 50 years and older should receive the same doses as patients younger than 50 years (see section "Pharmacokinetics").

Busulfan Mylan in combination with fludarabine

Adults

Recommended dose and regimen:

• fludarabine administered as a single one-hour infusion at a dose of 30 mg/m² for 5 consecutive days or at a dose of 40 mg/m² body surface area for 4 consecutive days;
• Busulfan Mylan administered at a dose of 3.2 mg/kg body weight as a single three-hour infusion immediately after fludarabine for 2 or 3 consecutive days.

Children (0 to 17 years)

The safety and efficacy of the FlBu regimen in children have not been established.

Elderly patients

The use of the FlBu regimen in elderly patients has not been studied. However, according to published data, in over 500 patients aged ≥ 55 years who received FlBu conditioning therapy, efficacy outcomes were similar to those in younger patients. Dose adjustment was not required.

Patients with obesity

Adults

For patients with obesity, consideration should be given to dosing based on adjusted body mass index (ABMI).

Body mass index (BMI) is calculated as follows:

BMI for men [kg] = 50 + 0.91 × (height [cm] – 152);

BMI for women [kg] = 45 + 0.91 × (height [cm] – 152).

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

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

Children

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

Patients with renal impairment

Studies in patients with renal impairment have not been conducted. Since busulfan is moderately excreted in urine, dose adjustment in these patients is not required. However, caution is recommended during use (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, particularly in patients with severe hepatic impairment (see section "Special precautions for use").

Method of administration

The concentrate for solution for infusion Busulfan Mylan must be diluted prior to administration. The final concentration of busulfan should be approximately 0.5 mg/mL. The medicinal product Busulfan Mylan should be administered intravenously via a central catheter.

Precautions for handling the medicinal product

Procedures for proper preparation and disposal of cytotoxic medicinal products should be followed.

All preparation steps must be performed under strict aseptic conditions, preferably using a vertical laminar flow hood.

As with other cytotoxic agents, caution should be exercised during preparation and administration of busulfan:

• use of gloves and protective clothing is 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 Busulfan Mylan medicinal product to be diluted and the volume of diluent

Prior to administration, the Busulfan Mylan medicinal product 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 greater than the volume of the Busulfan Mylan medicinal product to achieve a final busulfan concentration of approximately 0.5 mg/mL.

Example calculation of the amount of Busulfan Mylan medicinal product and diluent:

• Amount of Busulfan Mylan medicinal product (A):

Y (kg) × D (mg/kg)	= A (ml)
6 (mg/ml)

where Y is the patient's body weight, D is the dose of busulfan

• Volume of diluent (B):

A (ml) × 10 = B (ml)

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

Preparation of infusion solution

Preparation of Busulfan Milly medication must be performed by healthcare professionals using sterile equipment.

To prepare the infusion solution, use a syringe with a needle not made of polycarbonate:

• using a syringe, withdraw the calculated volume of Busulfan Milly medication from the vial;
• transfer the contents of the syringe into an infusion bag (or syringe) already containing the calculated volume of diluent.

Always add Busulfan Milly medication to the diluent, not vice versa. Busulfan Milly medication 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 should be thoroughly mixed by gently inverting the infusion bag several times.

After dilution, each 1 ml of the infusion solution contains 0.5 mg of busulfan.

After dilution, Busulfan Milly medication should be a clear, colorless solution.

Instructions for use

The permanent 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 medication 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 Busulfan Milly medication should be administered over two or three hours, depending on the conditioning regimen.

Small volumes of the medication 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, pre-filled with the medication solution before the actual infusion begins, and then flushed with 0.9% sodium chloride injection solution (9 mg/ml) or 5% glucose injection solution.

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

Polycarbonate syringes must not be used for administration of Busulfan Milly medication.

Busulfan Milly medication is intended for single use only. Only clear, particle-free solutions should be used.

Diluted solution

Chemical and physical stability of the medication 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 20–25 °C;
• up to 15 hours after dilution when stored at 2–8 °C, followed by up to 3 hours at 20–25 °C (including infusion time).

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

Any unused medication and waste material must be disposed of in accordance with current regulatory requirements for cytotoxic agents.

Busulfan Milly must not be administered via intravenous bolus injection or injected into peripheral veins.

Each patient should receive anticonvulsant prophylactic medication to prevent seizures that may occur with high-dose busulfan.

Anticonvulsant medications should be administered prior to the first dose of Busulfan Milly and continued according to standard regimens in accordance with current guidelines throughout the treatment period.

It is recommended to initiate anticonvulsant therapy 12 hours before the start of treatment, continue during treatment, and maintain for up to 24 hours after the last dose of Busulfan Milly.

In clinical studies, adult patients and children received phenytoin or benzodiazepines for seizure prophylaxis (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

Children. Administer Busulfan Milly to children followed by cyclophosphamide (BuCy2) or melphalan (BuMel) as part of conditioning therapy prior to standard hematopoietic stem cell transplantation (HSCT), according to the section "Dosage and administration".

The safety and efficacy of Busulfan Milly in combination with fludarabine in children have not been established.

Overdose

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

Currently, no specific antidote for busulfan is known other than hematopoietic stem cell transplantation (HSCT). If HSCT is not performed, the recommended dose of Busulfan Milly 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.

There are two reported cases indicating that busulfan undergoes dialysis, and therefore dialysis should be considered as a potential intervention in cases of overdose. Since busulfan is metabolized via glutathione conjugation, glutathione administration may be considered.

It should be noted that overdose of Busulfan Milly also increases exposure to dimethylacetamide (DMA). The main toxic effects of DMA in humans include hepatotoxicity and CNS effects. CNS disturbances may precede the development of other, more serious adverse effects. There is no known specific antidote for dimethylacetamide. In cases of overdose, general supportive measures should be implemented.

Adverse Reactions

Summary of the drug safety study results

Busulfan in combination with cyclophosphamide or melphalan

Adults

Data on adverse reactions are based on results from 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. These include infection and graft-versus-host disease (GVHD), which, although not directly related, were key causes of morbidity and mortality, particularly following allogeneic HSCT.

Blood and lymphatic system disorders. Myelosuppression and immunosuppression are desired therapeutic effects within conditioning therapy. Therefore, significant cytopenia was observed in all patients: leucopenia 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 transplants and 9 days for allogeneic transplants.

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

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 was fatal in 1% (1/103) and 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% of cases 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. 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 (fatal outcome in 2 patients) and in 2.5% (1/42) of autologous transplant recipients. Increased levels of bilirubin (n = 3) and aspartate aminotransferase (AST) (n = 1) were also observed. Two 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, one patient was diagnosed with acute respiratory distress syndrome, leading to fatal respiratory failure on the background of interstitial pulmonary fibrosis.

Children

Data on adverse reactions were obtained from a clinical study in children (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 (a-GVHD) were obtained from allograft recipients (n = 28). a-GVHD developed in 14 patients (50%). The incidence of grade I–II a-GVHD was 46.4% (13/28), and grade III–IV a-GVHD was 3.6% (1/28). Chronic GVHD 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 recorded in 15% (4/27) of autologous and 7% (2/28) of allogeneic transplants, respectively. The disease did not result in fatalities, was not severe, and was treatable in all cases.

Busulfan in combination with fludarabine

Adults

The safety profile assessment of busulfan in combination with fludarabine is based on published data from clinical trials in which a total of 1,574 patients received FB as reduced-intensity conditioning (RIC) therapy prior to hematopoietic progenitor cell transplantation.

Myelosuppression and immunosuppression were considered desired therapeutic effects of conditioning therapy and therefore were not regarded as 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 (30.7–80.0%), Epstein-Barr virus reactivation (2.3–61%), bacterial infections (32.0–38.9%), and viral infections (1.3–17.2%).

Gastrointestinal disorders. The highest reported 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/reactivation. Hemorrhagic cystitis, particularly caused by viral infection, was reported with a frequency of 16–18.1%.

Hepatobiliary disorders. Hepatic veno-occlusive disease was reported with a frequency ranging from 3.9% to 15.4%.

Treatment-related mortality (TRM) or non-relapse mortality (NRM), reported within 100 days after 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

The frequency of the adverse reactions listed below is categorized as follows: 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).

Adverse reactions reported after marketing authorization are listed under the category "frequency not known."

Busulfan in combination with cyclophosphamide or melphalan

The adverse reactions listed below were observed in adults and children in more than isolated cases, classified by system organ class and frequency of occurrence. Within each frequency group, adverse reactions are listed in order of decreasing frequency and severity.

Organ system classification	Very common	Common	Uncommon	Frequency not known
Infections and infestations	Rhinitis, pharyngitis
Blood and lymphatic system disorders	Neutropenia, thrombocytopenia, febrile neutropenia, anemia, pancytopenia
Immune system disorders	Allergic reaction
Endocrine disorders				Hypogonadism **
Musculoskeletal and connective tissue disorders	Muscle pain, back pain, joint pain
Metabolism and nutrition disorders	Anorexia, hyperglycemia, hypocalcemia, hypokalemia, hypomagnesemia, hypophosphatemia	Hypokalemia
Psychiatric disorders	Anxiety, depression, insomnia	Confusion	Agitation, restlessness, hallucinations, excitement
Nervous system disorders	Headache, dizziness		Seizures, encephalopathy, cerebral palsy
Eye disorders				Cataract, corneal thinning, lens disorders ***
Cardiac disorders	Tachycardia	Arrhythmia, atrial fibrillation, cardiomegaly, pericardial effusion, pericarditis	Ventricular extrasystoles, bradycardia
Vascular disorders	Hypertension, hypotension, thrombosis, vasodilation		Femoral artery thrombosis, systemic capillary leak syndrome
Respiratory, thoracic and mediastinal disorders	Dyspnea, epistaxis, cough, hiccup	Hyperpnea, respiratory failure, alveolar hemorrhage, asthma, atelectasis, pleural effusion	Hypoxia	Interstitial lung disease **, pulmonary hypertension
Gastrointestinal disorders	Oral infection, diarrhea, abdominal pain, nausea, vomiting, dyspepsia, ascites, constipation, anal discomfort	Hematemesis, obstruction, esophagitis	Gastrointestinal hemorrhage	Teeth hypoplasia **
Hepatobiliary disorders	Hepatomegaly, jaundice	Hepatic veno-occlusive disease *
Skin and subcutaneous tissue disorders	Rash, pruritus, alopecia	Skin exfoliation, erythema, pigmentation disorder
Musculoskeletal and connective tissue disorders	Muscle pain, back pain, joint pain
Renal and urinary disorders	Dysuria, oliguria	Hematuria, moderate renal failure
Reproductive system and breast disorders				Premature menopause, ovarian dysfunction **
General disorders and administration site conditions	Asthenia, chills, fever, chest pain, edema, generalized swelling, pain, pain or inflammation at injection site, mucosal inflammation
Investigations	Increased aminotransferase activity, increased bilirubin level, increased gamma-glutamyl transferase (GGT) activity, increased alkaline phosphatase activity, increased body weight, abnormal breath sounds, increased creatinine level	Increased creatine kinase muscle activity, decreased ejection fraction

* hepatic veno-occlusive disease occurs more frequently in children

** reported post-marketing for intravenous busulfan

*** reported post-marketing for oral busulfan

Busulfan in combination with fludarabine

The adverse reactions listed below have been observed in adults and children in more than isolated cases, classified by system organ class and frequency. The frequency of individual adverse reactions is based on the highest incidence reported in published clinical trials using RIC regimens with a clearly defined patient population receiving FB, regardless of busulfan dosing regimens and endpoints.

Organ Classifications and Systems	Very Common	Common	Frequency Not Known
Infections and Infestations	Viral infections, cytomegalovirus activation, Epstein-Barr virus activation, bacterial infections	Invasive fungal infections, pulmonary infections	Brain abscess, cellulitis, sepsis
Blood and Lymphatic System Disorders			Febrile neutropenia
Metabolism and Nutrition Disorders	Hypoalbuminemia, electrolyte disturbances, hyperglycemia		Anorexia
Psychiatric Disorders			Confusion, disorientation, hallucinations
Nervous System Disorders		Headache, nervous system disorders	Intracranial hemorrhage, encephalopathy
Cardiac Disorders			Atrial fibrillation
Vascular Disorders		Hypertension
Respiratory, Thoracic and Mediastinal Disorders		Pulmonary hemorrhage	Respiratory failure
Gastrointestinal Disorders	Nausea, vomiting, diarrhea, esophagitis		Gastrointestinal hemorrhage, dental hypoplasia*
Hepatobiliary Disorders	Hepatic veno-occlusive disease		Jaundice, hepatic dysfunction
Skin and Subcutaneous Tissue Disorders		Rash
Renal and Urinary Disorders	Hemorrhagic cystitis **	Kidney disorders	Oliguria
General Disorders and Administration Site Conditions	Mucositis		Asthenia, edema, pain
Investigations	Increased aminotransferase activity, increased bilirubin levels, increased alkaline phosphatase activity	Increased creatinine levels	Increased lactate dehydrogenase levels, increased uric acid levels, increased urea levels, increased GGT activity, increased body weight

* reported in the post-marketing period

** including hemorrhagic cystitis caused by viral infection

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions

Store in the original packaging at 2–8 °C, in a place inaccessible to children.

Incompatibilities

As compatibility studies have not been conducted, busulfan must not be mixed with other medicinal products except those specified in the section "Method of administration and dosage."

Do not use polycarbonate syringes for administration of Busulfan Mili medicinal product.

Packaging. 10 mL in a vial, 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Shilpa Medikea Limited / Shilpa Medicare Limited.

Manufacturer's address and location of its operations.

Unit 4, Pharmaceutical Formulations SEZ, Plot Nos S-20 to S-26, Pharma SEZ, TSIIC, Green Industrial Park, Polepally, Jadcherla, Mahbubnagar, Telangana, 509301, India /
Unit-4, Pharmaceutical Formulations SEZ, Plot No's S-20 to S-26, Pharma SEZ, TSIIC, Green Industrial Park, Polepally, Jadcherla, Mahabооbnagar, Telangana, 509301, India.

Marketing Authorization Holder

Mili Healthcare Limited.

Address of the Marketing Authorization Holder

2nd floor, office premises, 4 Charterfield House, Castle Street, Taunton, Somerset, England, TA1 4AS, United Kingdom.