Bendamustine hydrochloride for injection

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BENDAMUSTINE HYDROCHLORIDE FOR INJECTION

Composition:

Active substance: bendamustine hydrochloride;

One vial contains 25 mg or 100 mg of bendamustine hydrochloride;

Excipient: mannitol (E 421).

Pharmaceutical form. Powder for preparation of a concentrate for solution for infusion.

Main physicochemical properties: lyophilized mass or powder, white to almost white.

Pharmacotherapeutic group

Antineoplastic agents. Alkylating agents. Bendamustine. ATC code L01A A09.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Bendamustine is a bifunctional derivative of mechlorethamine containing a purine-like benzimidazole ring. Mechlorethamine and its derivatives form electrophilic alkylating groups. These groups form covalent bonds with electron-rich nucleophilic structures, leading to the formation of interstrand cross-links in DNA. Bifunctional covalent binding may lead to cell death through multiple pathways. Bendamustine is active against both resting and dividing cells. The exact mechanism of action of bendamustine remains unknown.

Based on pharmacokinetic/pharmacodynamic data in adult patients with non-Hodgkin’s lymphoma (NHL), the incidence of nausea increased with increasing Cmax of bendamustine.

Cardiac Electrophysiology

The effect of bendamustine on the QTc interval was evaluated in 53 patients with indolent NHL and mantle cell lymphoma on Day 1 of Cycle 1, following administration of rituximab 375 mg/m² intravenously as an infusion, followed by a 30-minute intravenous infusion of bendamustine at a dose of 90 mg/m²/day. Mean changes exceeding 20 milliseconds were not observed within one hour after infusion. The potential delayed effect on the QT interval after one hour was not assessed.

Pharmacokinetics

Absorption

After single intravenous administration of bendamustine hydrochloride, maximum plasma concentration (Cmax) was typically achieved at the end of the infusion. Dose proportionality of bendamustine has not been studied.

Distribution

Plasma protein binding of bendamustine ranged from 94% to 96% and was independent of concentration within the range of 1 to 50 mcg/mL. The blood-to-plasma concentration ratio in humans ranged from 0.84 to 0.86 over a concentration range of 10 to 100 mcg/mL. The mean steady-state volume of distribution (Vss) for bendamustine was approximately 20–25 L.

Elimination

After a single intravenous infusion of bendamustine at a dose of 120 mg/m² over 1 hour, the intermediate elimination half-life (t½) of the parent compound is approximately 40 minutes. The mean terminal elimination half-lives of the two active metabolites, γ-hydroxybendamustine (M3) and N-desmethylbendamustine (M4), are approximately 3 hours and 30 minutes, respectively. The clearance of bendamustine in humans is approximately 700 mL/min.

Metabolism

Bendamustine is extensively metabolized via hydrolysis, oxidation, and conjugation. The primary metabolic pathway is hydrolysis, forming monohydroxybendamustine (HP1) and dihydroxybendamustine (HP2), which exhibit low cytotoxic activity in vitro. Two active metabolites, M3 and M4, are formed predominantly via CYP1A2 in vitro. Plasma concentrations of M3 and M4 are approximately 1/10 and 1/100 of the parent compound concentration, respectively.

Excretion

After intravenous infusion of radiolabeled bendamustine hydrochloride in patients with malignant tumors, approximately 76% of the administered dose was recovered. Of this amount, about 50% of the dose was excreted in urine (of which 3.3% was unchanged), and approximately 25% of the dose was excreted in feces. Less than 1% of the dose was detected in urine as metabolites M3 and M4, and less than 5% of the dose as HP2.

Specific Populations

Clinically significant effects on the pharmacokinetics of bendamustine were not observed based on age (31–84 years), sex, mild to moderate renal impairment (Clcr ≥30 mL/min), or hepatic dysfunction with total bilirubin ≤1.5 × upper limit of normal (ULN) and AST or ALT <2.5 × ULN. The effect of severe renal impairment (Clcr <30 mL/min) or hepatic dysfunction with total bilirubin of 1.5–3 × ULN and AST or ALT 2.5–10 × ULN, or total bilirubin >3 × ULN on the pharmacokinetics of bendamustine is unknown.

Racial/Ethnic Group

Exposure to bendamustine in patients of East Asian ancestry (n=6) was 40% higher compared to patients of other races receiving the same dose. The clinical significance of this difference for the safety and efficacy of bendamustine hydrochloride in patients of East Asian ancestry has not been established.

Drug Interaction Studies

In vitro studies

Effect of bendamustine on CYP substrates

Bendamustine does not inhibit CYP1A2, 2C9/10, 2D6, 2E1, or 3A4/5. Bendamustine does not induce metabolism via CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5.

Effect of transporters on bendamustine hydrochloride

Bendamustine is a substrate of P-glycoprotein and breast cancer resistance protein (BCRP).

Clinical characteristics

Indications

Bendamustine hydrochloride for injection is an alkylating medicinal product indicated for the treatment of patients with:

• chronic lymphocytic leukemia (CLL). Efficacy compared to first-line therapy, excluding chlorambucil, has not been established;
• indolent B-cell non-Hodgkin’s lymphoma (NHL) with disease progression during or within 6 months after treatment with rituximab or rituximab-containing therapy.

Contraindications

Bendamustine hydrochloride is contraindicated in patients with known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine (see section "Special precautions").

Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on bendamustine hydrochloride

CYP1A2 inhibitors

Concomitant administration of bendamustine hydrochloride with CYP1A2 inhibitors may increase plasma concentrations of bendamustine and lead to an increased frequency of adverse reactions associated with bendamustine hydrochloride (see section "Pharmacokinetics"). Alternative therapies with medicinal products that are not CYP1A2 inhibitors should be considered during treatment with bendamustine hydrochloride.

CYP1A2 inducers

Concomitant administration of bendamustine hydrochloride with CYP1A2 inducers may reduce plasma concentrations of bendamustine and lead to decreased efficacy of bendamustine hydrochloride (see section "Pharmacokinetics"). Alternative therapies with medicinal products that are not CYP1A2 inducers should be considered during treatment with bendamustine hydrochloride.

Special precautions for use

Myelosuppression

Bendamustine hydrochloride caused severe myelosuppression (grade 3–4) in 98% of patients in two clinical trials in non-Hodgkin’s lymphoma (see section "Adverse reactions"). Three fatal cases (2%) due to adverse reactions associated with myelosuppression have been reported: neutropenic sepsis, diffuse alveolar haemorrhage on the background of grade III thrombocytopenia, and pneumonia caused by opportunistic infection. Complete blood counts, including white blood cell count, platelets, haemoglobin (Hgb), and absolute neutrophil count, should be monitored frequently. In clinical trials, blood monitoring was performed weekly. The lowest haematological values were predominantly observed during week 3 of therapy.

Dose delays or reductions may be required in cases of pronounced myelosuppression if counts have not recovered to recommended levels before the start of the next treatment cycle. Before initiating the next treatment cycle, the absolute neutrophil count should be ≥ 1 × 10⁹/L and platelet count should be ≥ 75 × 10⁹/L (see section "Dosage and administration").

Infections

Cases of infections, including pneumonia, sepsis, septic shock, hepatitis, and fatal outcomes, have been reported in adults and children during clinical trials and in post-marketing reports (see section "Adverse reactions"). Patients with myelosuppression following treatment with bendamustine hydrochloride are at increased risk of developing infections. Patients with myelosuppression due to bendamustine hydrochloride therapy should seek immediate medical attention if signs or symptoms of infection occur.

Patients receiving bendamustine hydrochloride may be at risk of reactivation of latent infections, including (but not limited to) hepatitis B, cytomegalovirus infection, Mycobacterium tuberculosis infection, and herpes zoster. Appropriate preventive measures to control infections and their reactivation, including clinical and laboratory monitoring, prophylaxis, and treatment when necessary, should be implemented before initiating therapy.

Progressive multifocal leukoencephalopathy (PML)

Cases of progressive multifocal leukoencephalopathy (PML), including fatal cases, have been reported following the use of bendamustine, primarily in combination with rituximab or obinutuzumab (see section "Adverse reactions"). PML should be considered in the differential diagnosis of patients presenting with new or worsening neurological, cognitive, or behavioural signs or symptoms. Appropriate diagnostic investigations should be performed and treatment should be suspended if PML is suspected.

In patients with confirmed PML, discontinuation or dose reduction of any concomitant chemotherapy or immunosuppressive therapy should be considered.

Anaphylaxis and infusion reactions

Infusion reactions to bendamustine occurred frequently in clinical trials (see section "Adverse reactions"). Symptoms were usually mild and included fever, chills, pruritus, and rash. Severe anaphylactic and anaphylactoid reactions occurred rarely, particularly during the second and subsequent treatment cycles. Clinical monitoring is required, and the drug should be discontinued in the event of severe adverse reactions. After the first treatment cycle, patients should be questioned about any history of symptoms suggestive of infusion reactions. Re-administration of this medicinal product is not recommended in patients who have experienced grade III or higher allergic reactions. For patients who previously experienced grade I or II infusion reactions, preventive measures, including the use of antihistamines, antipyretics, and corticosteroids, should be considered in subsequent treatment cycles. Administration of bendamustine hydrochloride should be discontinued in patients who experience grade IV infusion reactions. Treatment may be discontinued in cases of grade III infusion reactions, if clinically appropriate, considering the individual benefit-risk ratio and supportive therapy provided.

Tumour lysis syndrome

Tumour lysis syndrome associated with bendamustine treatment has been observed in patients during clinical trials and in the post-marketing period (see section "Adverse reactions"). The syndrome typically develops during the first cycle of bendamustine hydrochloride therapy and, if untreated, may lead to acute renal failure and death. Preventive measures include intensive hydration and careful monitoring of blood biochemical parameters, particularly potassium and uric acid levels. Allopurinol may be considered at the beginning of bendamustine therapy. However, concomitant use of bendamustine and allopurinol may increase the risk of severe skin toxicity (see section "Interaction with other medicinal products and other forms of interaction").

Skin reactions

Serious and fatal skin reactions have been reported during bendamustine treatment in clinical trials and in post-marketing surveillance, including severe skin toxicity [Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)], bullous exanthema, and rash (see section "Adverse reactions"). Some of these reactions occurred with both monotherapy and combination therapy with other antineoplastic agents or allopurinol.

Skin reactions may progress and worsen if treatment is continued. Patients with skin reactions should be closely monitored. Bendamustine hydrochloride should be withheld or discontinued in cases of progressive or severe skin reactions.

Hepatotoxicity

Fatal and serious cases of liver injury have been reported with bendamustine hydrochloride (see section "Adverse reactions"). In some patients, contributing factors included combination therapy, disease progression, or reactivation of hepatitis B. Most cases occurred within the first three months of therapy initiation. Monitoring of liver function biochemical parameters is recommended before and during treatment with bendamustine hydrochloride.

Other malignancies

There are reports of pre-malignant and malignant conditions in patients who received bendamustine hydrochloride, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukaemia, bronchial carcinoma, and non-melanoma skin cancer, including basal cell carcinoma and squamous cell carcinoma (see section "Adverse reactions"). Careful monitoring for secondary malignant neoplasms is recommended in patients. Periodic skin examinations should be performed in all patients during and after treatment.

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) was observed in patients receiving bendamustine therapy in clinical trials. Periodic skin examinations are recommended for all patients, particularly those with risk factors for skin cancer.

Extravasation

Cases of bendamustine hydrochloride extravasation have been reported, leading to hospitalisation due to erythema, marked swelling, and pain (see section "Adverse reactions"). Before initiating bendamustine hydrochloride infusion, a reliable venous access should be established, and the infusion site should be continuously monitored for redness, swelling, pain, signs of infection, and necrosis during and after infusion.

Embryo-fetal toxicity

Based on reproductive toxicity studies in animals and the mechanism of action of the drug, bendamustine hydrochloride may cause harm to the foetus when administered to pregnant women. Single intraperitoneal doses of bendamustine (approximately equivalent to the maximum recommended human dose based on body surface area) administered to pregnant mice and rats during organogenesis resulted in adverse developmental effects, including increased resorption rates, skeletal and visceral developmental abnormalities, and reduced foetal body weight.

Women should be informed of the potential risk to the foetus. Women of reproductive potential should use effective contraception to prevent pregnancy during treatment and for 6 months after the last dose. Men with partners of reproductive potential are advised to use effective contraception during therapy and for 3 months after the last dose of bendamustine hydrochloride (see section "Use during pregnancy or breastfeeding").

Use during pregnancy or breastfeeding

Pregnancy

Overview of risks

In reproductive studies in animals, intraperitoneal administration of bendamustine to pregnant mice and rats during organogenesis at doses 0.6–1.8 times the maximum recommended human dose caused embryo-/foetolethal effects, structural abnormalities, and growth impairment.

There are no data on the use of bendamustine hydrochloride in pregnant women, so it is not possible to assess the risk of major congenital malformations, miscarriage, or adverse outcomes for the mother or foetus associated with the drug. Women should be informed about the potential risk to the unborn child. The expected background risk of major congenital malformations and miscarriage in this population is unknown. All pregnancies carry a certain risk of congenital malformations, pregnancy loss, or other adverse outcomes. In the general US population, the estimated background risk of major congenital malformations in clinically recognised pregnancies is 2–4%, and the risk of miscarriage is 15–20%.

Breastfeeding

There are no data on the presence of bendamustine hydrochloride or its metabolites in breast milk, its effects on the breastfed child, or its effects on lactation. Due to the risk of serious adverse reactions in the breastfed child, breastfeeding is not recommended during treatment with bendamustine hydrochloride and for 1 week after the last dose.

Contraception

Before initiating treatment with bendamustine hydrochloride, women of childbearing potential should be tested for pregnancy.

Women

Bendamustine hydrochloride may cause harm to the embryo and foetus when administered to pregnant women. Women of reproductive potential should use effective contraception during treatment and for 6 months after the last dose of bendamustine hydrochloride.

Men

Based on genotoxicity data of bendamustine hydrochloride, men with partners of reproductive potential are advised to use effective contraception during treatment and for 3 months after the last dose of the drug.

Fertility

Men

Based on clinical trial data, bendamustine hydrochloride may impair male fertility. In male patients receiving alkylating agents, particularly in combination with other antineoplastic drugs, impaired spermatogenesis, azoospermia, and complete germinal aplasia have been reported. Spermatogenesis recovery may occur in some patients in remission, but this may take several years after completion of intensive chemotherapy. Patients should be informed about the potential risk to their reproductive capacity.

Animal studies have shown that bendamustine hydrochloride may impair male fertility, particularly due to an increased number of morphologically abnormal spermatozoa. The long-term impact of bendamustine hydrochloride on male fertility, including reversibility of adverse effects, has not been studied.

Ability to affect reaction speed when driving or operating machinery

Bendamustine has a significant influence on the ability to drive and operate machinery. During treatment with bendamustine, ataxia, peripheral neuropathy, and somnolence have been reported (see section "Adverse reactions"). Patients should be advised to avoid driving or operating machinery if these reactions occur.

Administration and Dosage

Bendamustine hydrochloride for injection is available as a lyophilized powder. The concentration of bendamustine hydrochloride in the reconstituted solution of the lyophilized powder is 5 mg/mL.

Monotherapy for Chronic Lymphocytic Leukemia (CLL)

Recommended Dosage

The medicinal product should be administered at a dose of 100 mg/m² intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle; up to 6 cycles.

Delay, Dose Modification, and Reinitiation of Therapy in CLL

Administration of bendamustine hydrochloride should be discontinued in the event of Grade IV hematologic toxicity or clinically significant non-hematologic toxicity ≥Grade II. After recovery of non-hematologic toxicity to ≤Grade I and/or improvement in blood counts (ANC ≥1 × 10⁹/L, platelets ≥75 × 10⁹/L), administration of bendamustine hydrochloride may be resumed at the physician’s discretion. Dose reduction should be considered if necessary (see section "Special Warnings and Precautions for Use").

Dose Adjustment for Hematologic Toxicity

In case of Grade III or higher toxicity — reduce dose to 50 mg/m² on Days 1 and 2 of each cycle.

In case of recurrent Grade III or higher toxicity — reduce dose to 25 mg/m² on Days 1 and 2 of each cycle.

Dose Adjustment for Non-Hematologic Toxicity

In case of clinically significant Grade III or higher toxicity — reduce dose to 50 mg/m² on Days 1 and 2 of each cycle.

Dose re-escalation may be considered in subsequent cycles at the physician’s discretion.

Monotherapy for Indolent Non-Hodgkin’s Lymphoma, Refractory to Rituximab

Recommended Dosage

The medicinal product should be administered at a dose of 120 mg/m² intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle; up to 8 cycles.

Delay, Dose Modification, and Reinitiation of Therapy in NHL

Administration of bendamustine hydrochloride should be discontinued in the event of Grade IV hematologic toxicity or clinically significant non-hematologic toxicity ≥Grade II. After recovery of non-hematologic toxicity to ≤Grade I and/or improvement in blood counts (ANC ≥1 × 10⁹/L, platelets ≥75 × 10⁹/L), administration of the medicinal product may be resumed at the physician’s discretion. Dose reduction should be considered (see section "Special Warnings and Precautions for Use").

Dose Adjustment for Hematologic Toxicity

In case of Grade IV toxicity — reduce dose to 90 mg/m² on Days 1 and 2 of each cycle.

In case of recurrent Grade IV or higher toxicity — reduce dose to 60 mg/m² on Days 1 and 2 of each cycle.

Dose Adjustment for Non-Hematologic Toxicity

In case of Grade III or higher toxicity — reduce dose to 90 mg/m² on Days 1 and 2 of each cycle.

In case of recurrent Grade III or higher toxicity — reduce dose to 60 mg/m² on Days 1 and 2 of each cycle.

Instructions for Preparation of Infusion Solution

Bendamustine hydrochloride is a potentially hazardous medicinal product. Special handling and disposal procedures must be followed. Each vial of bendamustine hydrochloride for injection is intended for single use only.

The vial of bendamustine hydrochloride for injection should be reconstituted aseptically as follows:

• Add 5 mL of Water for Injections to the vial containing 25 mg of bendamustine hydrochloride, then shake the vial.
• Add 20 mL of Water for Injections to the vial containing 100 mg of bendamustine hydrochloride, then shake the vial.

The vial should be shaken thoroughly until a clear, colorless to pale yellow solution with a concentration of 5 mg/mL is obtained. The lyophilized powder should dissolve completely within 5 minutes. The solution should be transferred to an infusion container within 30 minutes after preparation. Do not use the medicinal product if visible particles are present.

Aseptically withdraw the required volume of solution (based on a concentration of 5 mg/mL) and immediately transfer it into a 500 mL infusion bag containing 0.9% sodium chloride solution. Alternatively, a 500 mL infusion bag containing 2.5% glucose / 0.45% sodium chloride solution may be used. The final concentration of bendamustine hydrochloride in the infusion bag should be between 0.2–0.6 mg/mL. After transfer, the solution should be mixed thoroughly.

Visual inspection of the solution for particulate matter and discoloration should be performed prior to administration. The final solution should be clear, colorless or slightly yellowish, and practically free from visible particles.

Only sterile Water for Injections should be used for reconstitution, and 0.9% sodium chloride solution or 2.5% glucose / 0.45% sodium chloride solution should be used for dilution. Other solvents have not been evaluated for compatibility.

Parenteral medicinal products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit. Unused solution should be disposed of according to cytotoxic waste handling procedures.

Stability of Prepared Solution

Bendamustine hydrochloride for injection does not contain antimicrobial preservatives. The solution should be prepared as close as possible to the time of administration.

After dilution with 0.9% sodium chloride solution or 2.5% glucose / 0.45% sodium chloride solution, the final solution is stable for 24 hours when stored refrigerated at 2–8 °C or for 3 hours at room temperature (15–30 °C) under normal lighting conditions. Administration of the medicinal product should be completed within this time frame.

Use in Elderly Patients

No overall differences in safety were observed between patients aged ≥65 years and younger patients. Efficacy was lower in patients aged 65 years and older with CLL receiving bendamustine hydrochloride, based on an overall response rate of 47% in patients aged ≥65 years versus 70% in younger patients. Progression-free survival was also longer in younger CLL patients receiving bendamustine hydrochloride (19 months vs. 12 months). No overall differences in efficacy were observed between elderly and younger patients with NHL.

Use in Patients with Hepatic Impairment

Do not administer bendamustine hydrochloride to patients with AST or ALT levels of 2.5–10 × upper limit of normal (ULN) and total bilirubin of 1.5–3 × ULN, or with total bilirubin >3 × ULN.

Use in Patients with Renal Impairment

Do not administer bendamustine hydrochloride to patients with creatinine clearance <30 mL/min.

Children

The medicinal product should not be used in children due to lack of data on efficacy and safety.

Overdose

The intravenous lethal dose (LD₅₀) of bendamustine hydrochloride is 240 mg/m² in mice and rats. The main manifestations of toxicity included sedation, tremor, ataxia, convulsions, and respiratory distress.

Based on clinical experience, the highest single dose administered was 280 mg/m². In three out of four patients receiving this dose, ECG changes considered dose-limiting were observed on Day 7 and Day 21 after administration. These changes included QT interval prolongation (one patient), sinus tachycardia (one patient), ST and T wave abnormalities (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fraction remained normal in all cases.

Treatment. There is no specific antidote. Management of overdose should include general supportive measures, including monitoring of hematological parameters and ECG.

Adverse Reactions

The following clinically significant adverse reactions have been observed with bendamustine hydrochloride in clinical trials and are described in detail in other sections of the instructions: myelosuppression, infections, progressive multifocal leukoencephalopathy, anaphylaxis and infusion reactions, tumor lysis syndrome, skin reactions, hepatotoxicity, secondary malignancies, and extravasation injury (see section "Special Warnings and Precautions for Use"). Since clinical trials are conducted under different conditions, the frequency of adverse reactions observed in clinical trials of a particular medicinal product may not be directly comparable to frequencies observed in other trials and does not necessarily reflect the frequencies observed in routine medical practice.

Chronic Lymphocytic Leukemia (CLL)

The data presented below are based on the experience of using bendamustine hydrochloride in 153 patients enrolled in an active-controlled, randomized, clinical trial. The study population included patients aged 45 to 77 years; 63% were male, all were Caucasian, with newly diagnosed chronic lymphocytic leukemia (CLL) who had not received prior therapy. Initial treatment was administered at a dose of 100 mg/m² intravenously over 30 minutes on days 1 and 2 of each 28-day cycle.

Adverse reactions were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTC). In the randomized trial in CLL, the most common non-hematologic adverse reactions of any severity occurring at a frequency >15% in the bendamustine hydrochloride group were: fever (24%), nausea (20%), and vomiting (16%).

Other commonly reported adverse reactions observed in one or more studies included: asthenia, increased fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation, and stomatitis. Worsening of arterial hypertension was reported in 4 patients receiving bendamustine hydrochloride (no such cases were reported in the chlorambucil group). In 3 out of 4 patients, the adverse reaction was classified as hypertensive crisis; all cases were managed with oral antihypertensive medications and subsequently resolved. The most common reasons for discontinuation of treatment with bendamustine hydrochloride were hypersensitivity (2%) and fever (1%).

Table 1 presents data on non-hematologic adverse reactions observed in ≥5% of patients in either treatment group in the randomized clinical trial of CLL.

Table 1

Non-hematologic adverse reactions occurring in the randomized clinical trial of CLL in ≥5% of patients

	Number of patients (%)
	Bendamustine hydrochloride for injection (N=153)		Chlorambucil (N=143)
Organ system / Adverse reaction	All grades	Grade III/IV	All grades	Grade III/IV
Total number of patients with ≥1 adverse reaction	121 (79%)	52 (34%)	96 (67%)	25 (17%)
Gastrointestinal disorders
Nausea	31 (20%)	1 (<1%)	21 (15%)	1 (<1%)
Vomiting	24 (16%)	1 (<1%)	9 (6%)	0
Diarrhea	14 (9%)	2 (1%)	5 (3%)	0
General disorders
Pyrexia	36 (24%)	6 (4%)	8 (6%)	2 (1%)
Fatigue	14 (9%)	2 (1%)	8 (6%)	0
Asthenia	13 (8%)	0	6 (4%)	0
Chills	9 (6%)	0	1 (<1%)	0
Immune system disorders
Hypersensitivity	7 (5%)	2 (1%)	3 (2%)	0
Infections and infestations
Nasopharyngitis	10 (7%)	0	12 (8%)	0
Infection	9 (6%)	3 (2%)	1 (<1%)	1 (<1%)
Herpes simplex	5 (3%)	0	7 (5%)	0
Laboratory investigations
Weight decreased	11 (7%)	0	5 (3%)	0
Metabolism and nutrition disorders
Hyperuricemia	11 (7%)	3 (2%)	2 (1%)	0
Respiratory system disorders
Cough	6 (4%)	1 (<1%)	7 (5%)	1 (<1%)
Skin and subcutaneous tissue disorders
Rash	12 (8%)	4 (3%)	7 (5%)	3 (2%)
Pruritus	8 (5%)	0	2 (1%)	0

The hematological laboratory abnormalities of Grade III and IV by treatment groups in the randomized clinical trial of CLL are described in Table 2. These results confirm the myelosuppressive effects observed in patients receiving bendamustine hydrochloride. Red blood cell transfusions were administered to 20% of patients receiving bendamustine hydrochloride, compared to 6% of patients receiving chlorambucil.

Table 2

Frequency of hematological laboratory abnormalities in patients with CLL

	Bendamustine hydrochloride for injection (N=153)		Chlorambucil (N=143)
Laboratory abnormalities	Any grade n (%)	Grade III/IV n (%)	Any grade n (%)	Grade III/IV n (%)
Decreased hemoglobin levels	134 (89 %)	20 (13 %)	115 (82 %)	12 (9 %)
Decreased platelet levels	116 (77 %)	16 (11 %)	110 (78 %)	14 (10 %)
Decreased white blood cell levels	92 (61 %)	42 (28 %)	26 (18 %)	4 (3 %)
Decreased lymphocyte levels	102 (68 %)	70 (47 %)	27 (19 %)	6 (4 %)
Decreased neutrophil levels	113 (75 %)	65 (43 %)	86 (61 %)	30 (21 %)

In a randomized CLL study, elevated bilirubin levels were observed in 34 % of patients, some without concomitant significant increases in AST and ALT levels. Grade III or IV elevations in bilirubin were observed in 3 % of patients. Grade III or IV elevations in AST and ALT were limited to 1 % and 3 % of patients, respectively. In patients receiving bendamustine hydrochloride, changes in creatinine levels may also occur. If abnormalities are detected, these parameters should be monitored further to ensure that there is no further deterioration.

Non-Hodgkin’s Lymphoma (NHL)

The data presented below reflect the impact of bendamustine hydrochloride in 176 patients with indolent B-cell NHL treated in two single-arm studies. Patient age ranged from 31 to 84 years, 60 % were men and 40 % were women. The racial distribution was: 89 % White, 7 % Black, 3 % Hispanic, 1 % other, and <1 % Asian. These patients received bendamustine hydrochloride at a dose of 120 mg/m² administered intravenously on Days 1 and 2 of up to eight 21-day cycles.

Adverse reactions occurring in at least 5 % of NHL patients, regardless of severity, are listed in Table 3. The most common non-hematological adverse reactions (≥30 %) were nausea (75 %), fatigue (57 %), vomiting (40 %), diarrhea (37 %), and pyrexia (34 %). The most common non-hematological adverse reactions of Grade III or IV severity (≥5 %) were fatigue (11 %), febrile neutropenia (6 %), pneumonia, hypokalemia, and dehydration, each observed in 5 % of patients.

Table 3

Non-hematological adverse reactions occurring in at least 5 % of NHL patients treated with bendamustine hydrochloride (N=176).

Organ systems / Adverse reaction	Number of patients (%)*
	All grades	Grade III/IV
Total number of patients with at least 1 adverse reaction	176 (100)	94 (53)
Cardiac disorders
Tachycardia	13 (7)	0
Gastrointestinal disorders
Nausea	132 (75)	7 (4)
Vomiting	71 (40)	5 (3)
Diarrhea	65 (37)	6 (3)
Constipation	51 (29)	1 (<1)
Stomatitis	27 (15)	1 (<1)
Abdominal pain	22 (13)	2 (1)
Dyspepsia	20 (11)	0
Gastroesophageal reflux disease	18 (10)	0
Dry mouth	15 (9)	1 (<1)
Upper abdominal pain	8 (5)	0
Abdominal distension	8 (5)	0
General disorders and administration site conditions
Fatigue	101 (57)	19 (11)
Fever	59 (34)	3 (2)
Chills	24 (14)	0
Peripheral edema	23 (13)	1 (<1)
Asthenia	19 (11)	4 (2)
Chest pain	11 (6)	1 (<1)
Infusion site pain	11 (6)	0
Pain	10 (6)	0
Catheter site pain	8 (5)	0
Infections and infestations
Herpes zoster	18 (10)	5 (3)
Upper respiratory tract infection	18 (10)	0
Urinary tract infection	17 (10)	4 (2)
Sinusitis	15 (9)	0
Pneumonia	14 (8)	9 (5)
Febrile neutropenia	11 (6)	11 (6)
Oral candidiasis	11 (6)	2 (1)
Nasopharyngitis	11 (6)	0
Laboratory investigations
Weight decreased	31 (18)	3 (2)
Metabolism and nutrition disorders
Anorexia	40 (23)	3 (2)
Dehydration	24 (14)	8 (5)
Decreased appetite	22 (13)	1 (<1)
Hypokalemia	15 (9)	9 (5)
Musculoskeletal and connective tissue disorders
Back pain	25 (14)	5 (3)
Arthralgia	11 (6)	0
Limb pain	8 (5)	2 (1)
Bone pain	8 (5)	0
Nervous system disorders
Headache	36 (21)	0
Dizziness	25 (14)	0
Dysgeusia	13 (7)	0
Psychiatric disorders
Insomnia	23 (13)	0
Anxiety	14 (8)	1 (<1)
Depression	10 (6)	0
Respiratory, thoracic and mediastinal disorders
Cough	38 (22)	1 (<1)
Dyspnea	28 (16)	3 (2)
Throat/sore throat	14 (8)	1 (<1)
Wheezing	8 (5)	0
Nasal congestion	8 (5)	0
Skin and subcutaneous tissue disorders
Rash	28 (16)	1 (<1)
Pruritus	11 (6)	0
Dry skin	9 (5)	0
Night sweats	9 (5)	0
Hyperhidrosis	8 (5)	0
Vascular disorders
Hypotension	10 (6)	2 (1)

* Patients could have reported more than one adverse reaction.

Note. Each patient was counted only once within each category of adverse reactions and only once within each body system category.

Hematologic toxicity, assessed by laboratory parameters and severity grading according to the CTC (Common Toxicity Criteria) classification developed by the U.S. National Cancer Institute, in NHL patients who received treatment in the combined analysis of two single-arm studies, is presented in Table 4.

Clinically significant biochemical laboratory abnormalities that were either new or worsened from baseline and observed in >1% of NHL patients (Grade III or IV) in the combined analysis included:

• hyperglycemia (3%),
• increased creatinine (2%),
• hyponatremia (2%),
• hypocalcemia (2%).

Table 4

Frequency of hematologic laboratory parameter abnormalities in patients who received bendamustine hydrochloride in NHL studies.

Hematological parameter	Percentage of patients
	All grades (%)	Grades III/IV (%)
Lymphocyte count decreased	99	94
Leukocyte count decreased	94	56
Hemoglobin decreased	88	11
Neutrophil count decreased	86	60
Platelet count decreased	86	25

In both studies, serious adverse reactions, regardless of causal relationship, were observed in 37% of patients receiving bendamustine hydrochloride. The most common serious adverse reactions occurring in ≥5% of patients were febrile neutropenia and pneumonia.

Other clinically significant serious adverse reactions reported in clinical studies and/or during post-marketing use included: acute renal failure, heart failure, hypersensitivity, skin reactions, pulmonary fibrosis, myelodysplastic syndrome. Serious adverse reactions related to bendamustine hydrochloride therapy and observed in clinical studies included myelosuppression, infections, pneumonia, tumor lysis syndrome, and infusion reactions. Less frequently observed adverse reactions potentially related to bendamustine hydrochloride therapy included hemolysis, dysgeusia (taste disturbance), atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis.

Post-marketing experience with bendamustine

During post-marketing use of bendamustine hydrochloride, the following adverse reactions have been identified. Because these reports are voluntarily submitted from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: pancytopenia.

Cardiac disorders: atrial fibrillation, congestive heart failure (some cases fatal), myocardial infarction (some cases fatal), palpitations.

General disorders and administration site conditions: injection site reactions (including phlebitis, pruritus, irritation, pain, swelling), infusion site reactions (including phlebitis, pruritus, irritation, pain, swelling).

Immune system disorders: anaphylaxis.

Infections and infestations: Pneumocystis jiroveci pneumonia; progressive multifocal leukoencephalopathy (PML).

Renal and urinary disorders: nephrogenic diabetes insipidus (NDI). Respiratory, thoracic and mediastinal disorders: pneumonitis. Skin and subcutaneous tissue disorders: drug reaction with eosinophilia and systemic symptoms (DRESS), non-melanoma skin cancer, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN).

Reporting of suspected adverse reactions

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

Shelf life. 2 years.

Storage conditions

Store in the original packaging, protected from light, at a temperature not exceeding 25 ºC. Keep out of reach of children.

Packaging. 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer

Yugia Pharma Specialities Limited

Manufacturer's address and location of its operations

Unit-1, Survey No. 550, 551 and 552, Koltur Village, Shamirpet Mandal, Medchal – Malkajgiri, Medchal District, Telangana 500101 – India.