Indications for use
Chronic lymphocytic leukemia (CLL)
For the treatment of patients with chronic lymphocytic leukemia. Efficacy has been established relative to first-line therapy, except for chlorambucil.
Non-Hodgkin’s lymphoma (NHL)
For the treatment of patients with indolent B-cell non-Hodgkin’s lymphoma that developed during or within six months of treatment with rituximab or rituximab-containing drugs.

List of information required before starting treatment
Contraindications
hypersensitivity to the active substance or excipients (mannitol)
children and adolescents under 18 years of age
pregnancy and lactation
moderate and severe liver failure (bilirubin> 3.0 mg / dl)
jaundice
white blood cell count less than 3000 / μl and / or platelet count less than 75,000 / μl
surgery less than 30 days before starting therapy
infections, especially those accompanied by leukopenia
vaccination against yellow fever

Necessary precautions for use
Myelosuppression
There is a possibility that patients receiving treatment with bendamustine hydrochloride may experience myelosuppression. In case of treatment-related myelosuppression, careful monitoring of white blood cells, platelets, hemoglobin (Hb), and neutrophils should be performed weekly.
Hematological nadir in neutrophils occurred predominantly in the third week of treatment. Chemotherapy-related hematological nadir in neutrophils may require interruption of treatment if recovery to recommended values has not occurred by the first day of the next scheduled cycle. Before starting the next treatment cycle, the absolute neutrophil count should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L.
Infections
Serious and fatal infections, including bacterial (sepsis, pneumonia), opportunistic infections such as Pneumocystis jirovecii pneumonia, varicella-zoster virus, and cytomegalovirus, have been reported with bendamustine hydrochloride. Treatment with bendamustine hydrochloride may cause prolonged lymphocytopenia (<600/µL) and low CD4-positive T-lymphocyte (T-helper) counts (<200/µL) for at least 7-9 months after completion of treatment. Lymphocytopenia and CD4-positive T-lymphocyte depletion are more pronounced when bendamustine is combined with rituximab. Patients with lymphopenia and low CD4-positive T-cell counts after treatment with bendamustine hydrochloride are more susceptible to (opportunistic) infections. In case of low CD4-positive T-cell counts (<200/µL), Pneumocystis carinii pneumonia prophylaxis should be considered.
All patients should be monitored for respiratory symptoms during treatment. Patients should be instructed to promptly report any new signs of infection, including fever or respiratory symptoms.
Infusion reactions and anaphylaxis
Infusion reactions to bendamustine hydrochloride have occurred in routine clinical trials. Symptoms include fever, chills, pruritus, and rash. Rarely, serious anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent treatment cycles. Close clinical monitoring is necessary and, in the event of severe reactions, the drug should be discontinued. Patients should be asked about symptoms suggestive of infusion reactions after the first treatment cycle. In subsequent cycles, measures to prevent serious reactions, including antihistamines, antipyretics, and corticosteroids, should be considered for patients who have previously experienced grade 1 or 2 infusion reactions. Discontinuation of the drug should be considered for patients with grade 3 or 4 infusion reactions.
Tumor lysis syndrome
Tumor lysis syndrome associated with bendamustine hydrochloride treatment has been observed with bendamustine hydrochloride. Onset of action typically occurs within the first cycle (within 48 hours) of bendamustine hydrochloride treatment and, without intervention, may result in acute renal failure and death. Preventive measures include adequate hydration and careful monitoring of blood chemistry parameters, particularly potassium and uric acid levels, and consideration of hypouricemic agents (allopurinol and rasburicase) prior to initiating therapy. A few cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with concomitant use of bendamustine and allopurinol.
Skin reactions
There have been reports of skin reactions. These events included rash, severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reactions with eosinophilia and systemic symptoms (DRESS)) and bullous exanthema. Some events occurred when bendamustine hydrochloride was used in combination with other antineoplastic agents, so the exact relationship between the drug and their development has not been established.
There have been reports of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with fatal outcomes, when bendamustine hydrochloride was administered concomitantly with allopurinol and other drugs known to cause these syndromes. The relationship with bendamustine hydrochloride has not been established.
If skin reactions occur, they may progress and increase in severity with continued treatment. Therefore, patients with skin reactions should be closely monitored. If skin reactions are severe or progressive, treatment with bendamustine hydrochloride should be discontinued.
Other Malignancies
There have been reports of premalignant and malignant lesions that have developed in patients treated with bendamustine hydrochloride, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma. An association with bendamustine hydrochloride treatment has not been established.
Extravasation
There have been postmarketing reports of bleeding events following administration of bendamustine hydrochloride, leading to hospitalization due to erythema, marked swelling, and pain. Precautions should be taken to avoid extravasation, including monitoring the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of bendamustine hydrochloride.
Pediatric Use
The efficacy and safety of bendamustine hydrochloride in pediatric patients has not been evaluated.
Geriatric Use
No clinically significant differences in adverse reactions have been identified between geriatric (≥ 65 years) and younger patients.
Renal Impairment
Bendamustine hydrochloride injection should be used with caution in patients with mild to moderate renal impairment. Bendamustine hydrochloride injection should not be used in patients with creatinine clearance <40 ml/min.
Hepatic Impairment
Bendamustine hydrochloride injection should be used with caution in patients with mild hepatic impairment. BENTERO should not be administered to patients with moderate (AST or ALT 2.5-10 x ULN and bilirubin 1.5-3 x ULN) or severe (total bilirubin > 3 x ULN) hepatic impairment.
Gender Effects
The pharmacokinetics of bendamustine hydrochloride were similar in male and female patients.
Hepatitis B Reactivation
Hepatitis B reactivation has occurred in patients who are chronic carriers of this virus after receiving bendamustine hydrochloride. Some cases have resulted in acute liver failure or death. Patients should be tested for HBV infection before starting bendamustine hydrochloride treatment. Before initiating treatment, consultation with a liver specialist and hepatitis B specialist should be sought in patients with positive hepatitis B tests (including active disease) and in patients with a positive test for HBV infection during treatment. In HBV carriers requiring treatment with bendamustine hydrochloride, careful monitoring for signs and symptoms of active HBV infection should be considered throughout therapy and for several months after stopping therapy.
Contraception
Bendamustine hydrochloride is teratogenic and mutagenic.
Women should be aware of the potential risk to the fetus. Female and male patients of reproductive potential should use effective contraception during treatment and for at least 6 months after the last dose.

Interactions with other medicinal products
No formal clinical evaluations of pharmacokinetic drug interactions between BENTERO and other medicinal products have been performed.
The active metabolites of bendamustine hydrochloride, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4), are formed by the cytochrome P450 CYP1A2. CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin) may potentially increase bendamustine plasma concentrations and increase the incidence of adverse reactions. CYP1A2 inducers (e.g., omeprazole, smoking) may potentially decrease bendamustine hydrochloride plasma concentrations and decrease the efficacy of BENTERO. Caution should be exercised when co-administering CYP1A2 inhibitors or inducers, or alternative treatment should be considered.
The role of the active transport system in the disposition of bendamustine hydrochloride has not been fully evaluated. Some data indicate that P-glycoprotein, breast cancer resistance protein (BCRP) and/or other efflux transporters may play a role in the transport of bendamustine hydrochloride.

Special warnings
Women of childbearing potential should use effective contraception before and during bendamustine hydrochloride therapy and for at least 6 months after the last dose. It is recommended that women of childbearing potential undergo pregnancy testing before starting treatment with BENTERO.
Pregnancy
Bendamustine hydrochloride injection may cause fetal harm when administered to pregnant women. There are insufficient data on the use of bendamustine hydrochloride in pregnant women. Bendamustine hydrochloride should not be used during pregnancy unless clearly needed. The mother should be apprised of the risk to the fetus. If treatment with bendamustine hydrochloride is absolutely necessary during pregnancy or if pregnancy occurs during treatment, the patient should be informed of the risks to the unborn child and be closely monitored. Genetic counseling should be considered.
Lactation
It is unknown whether BENTERO passes into human milk, therefore bendamustine hydrochloride is contraindicated during breastfeeding.
Breastfeeding should be discontinued during treatment with bendamustine hydrochloride.
Fertility
Bendamustine hydrochloride reduces male fertility. Patients should be informed of the potential hazard to their reproductive capacity.
Peculiarities of the drug's effect on the ability to drive vehicles or potentially dangerous machinery
Studies of the effect on the ability to drive vehicles or potentially dangerous machinery have not been conducted.

Directions for Use
Dosing regimen for CLL
The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on days 1 and 2 of a 28-day cycle, for up to 6 cycles.
Interruption of treatment, dose modification, and resumption of treatment in CLL
BENTERO should be interrupted (delayed) in the event of grade 4 hematological toxicity or clinically significant grade ≥ 2 non-hematological toxicity. Once non-hematological toxicity has resolved to grade ≤ 1 and/or blood count has improved [absolute neutrophil count (ANC) ≥ 1×109/L, platelets ≥ 75×109/L], bendamustine hydrochloride treatment may be resumed at the discretion of the treating physician. A dose reduction may be warranted.
Dose modification for hematologic toxicity
For grade 3 or higher toxicity, reduce the dose to 50 mg/m2 on days 1 and 2 of each cycle; if grade 3 toxicity recurs, reduce the dose to 25 mg/m2 on days 1 and 2 of each cycle.
Dose modification for non-hematologic toxicity
For clinically significant grade 3 or higher toxicity, reduce the dose to 50 mg/m2 on days 1 and 2 of each cycle.
At the discretion of the physician, further dose escalation may be considered in subsequent cycles.
Dosing regimen for NHL
The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on days 1 and 2 of a 21-day cycle for up to 8 cycles.
Treatment interruption, dose modification, and resumption in CLL
BENTERO should be interrupted (delayed) in case of grade 4 hematological toxicity or clinically significant non-hematological toxicity ≥ grade 2. Once non-hematological toxicity has recovered to ≤ grade 1 and/or blood count has improved [absolute neutrophil count (ANC) ≥ 1×109/L, platelets ≥ 75×109/L], bendamustine hydrochloride treatment may be resumed at the discretion of the treating physician. A dose reduction may be warranted.
Dose modification for hematological toxicity
For grade 4 toxicity, the dose should be reduced to 90 mg/m2 on days 1 and 2 of each cycle; If Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on days 1 and 2 of each cycle.
Dose modification for non-hematological toxicity
If toxicity greater than Grade 3 recurs, reduce the dose to 90 mg/m2 on days 1 and 2 of each cycle; if toxicity of Grade 3 or greater recurs, reduce the dose to 60 mg/m2 on days 1 and 2 of each cycle.
Dilution/Preparation for IV Administration
Under sterile conditions, reconstitute each BENTERO vial as follows:
 100 mg vial: add 20 mL of sterile water for injection only.
Shake well to obtain a clear, colorless to pale yellow solution containing 5 mg/mL bendamustine hydrochloride. The lyophilized powder should be completely dissolved within 5 minutes. If undissolved particles are observed, the diluted solution should not be used.
Under sterile conditions, withdraw the volume required for the required dose (based on a 5 mg/ml concentration) and immediately transfer to 500 ml infusion bag of 0.9% Saline Solution for Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP may be considered. The resulting final concentration of bendamustine hydrochloride in the infusion bag should be in the range of 0.2 - 0.6 mg/mL. The diluted solution should be poured into the infusion bag within 30 minutes of dilution. After pouring, mix the contents of the infusion bag thoroughly. The mixture should be clear and colorless to slightly yellow. Use Sterile Water for Injection for reconstitution, followed by either 0.9% Sodium Chloride Injection, USP or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP for dilution as described above. Other diluents are not compatible.
Parenteral products should be inspected visually for particulate matter and discoloration prior to administration, as soon as solution and container permit. Any unused solution should be discarded in accordance with regulatory procedures for antineoplastic drugs.
Stability of the Mixture: Bendamustine hydrochloride does not contain an antimicrobial preservative. The mixture should be prepared as close to the time of administration to the patient as possible. After dilution with 0.9% Sodium Chloride Injection, USP or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final mixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Bendamustine hydrochloride administration should be completed within this period.
Method and Route of Administration
Infusion.
Intravenous administration should be performed under the supervision of a physician suitably qualified and experienced in the administration of chemotherapeutic agents.
Overdose measures
Symptoms: Limiting toxicity has included confusion, lethargy, dizziness, cardiac dysfunction (including angina, tachyarrhythmia, palpitations, anxiety, and diaphoresis), dry mouth, and taste changes.
Days 7-21 may include ECG abnormalities including QT prolongation, sinus tachycardia, ST and T wave changes, and left anterior bundle branch block.
Treatment: Close monitoring of the patient, including hematological and ECG parameters. No specific antidote is known. Bone marrow transplantation, blood cell transfusions, or hematological growth factors may be effective in controlling hematologic adverse effects. Treatment is symptomatic. Dialysis is of little use.
Consult a physician for advice before using this medicinal product.

Description of adverse reactions that occur during standard use of the medicinal product and measures to be taken in this case
The frequency of adverse reactions is determined in accordance with
the following criteria: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), unknown (cannot be estimated from the available data)

Very common

• leukopenia NOS*, lymphopenia, thrombocytopenia, decreased hemoglobin, increased creatinine, increased urea
• fever, fatigue
• nausea, vomiting, decreased appetite, anorexia
• mucositis, abdominal pain, dyspepsia, hypokalemia
• headache
• back pain, arthralgia, pain in extremities, bone pain, weakness, weight loss
• hyperuricemia
• infection NOS*, including opportunistic infections (e.g. herpes zoster, cytomegalovirus, hepatitis B)

Common

• tumor lysis syndrome
• hypersensitivity NOS*
• bleeding, neutropenia, anaemia
• diarrhoea, constipation, stomatitis, gastroesophageal reflux, dry mouth, dysgeusia, increased alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin concentration
• cardiac dysfunction, in particular palpitations, angina, arrhythmia, hypotension, hypertension
• pulmonary dysfunction, cough, dyspnoea, wheezing, nasal congestion
• insomnia, dizziness
• anxiety, depression
• skin rash, pruritus, dry skin, increased night sweats
• amenorrhea
• pain, chills, dehydration, anorexia
• erythema, injection site pain
• peripheral oedema, hypokalemia
• alopecia, skin disorders NEC, urticaria

Uncommon

• upper respiratory tract infection, urinary tract infection, sinusitis, febrile neutropenia, oral candidiasis, nasopharyngitis, nasopharyngitis
• pneumocystis pneumonia
• myelodysplastic syndrome, acute myeloid leukemia
• pancytopenia
• pericardial effusion, myocardial infarction, acute heart failure

Rare

• increased somnolence, aphonia
• anaphylactic/anaphylactoid reactions
• necrosis of surrounding tissue after accidental extravasation
• sepsis
• acute circulatory failure
• bone marrow failure
• erythema, dermatitis, pruritus, maculopapular rash, hyperhidrosis

Very rare

• hemolysis
• hemorrhagic esophagitis, gastrointestinal bleeding
• tachycardia,
• pulmonary fibrosis, primary atypical pneumonia
• dysgeusia, paresthesia, peripheral sensory neuropathy, anticholinergic syndrome, neurological disorders, ataxia, encephalitis
• anaphylactic shock
• infertility
• multiple organ failure
• phlebitis

Unknown

• atrial fibrillation
• pneumonitis, pulmonary alveolar hemorrhage
• liver failure
• Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)*
• renal failure

NOS = not otherwise specified
(*=combination therapy with rituximab)

Description of selected adverse reactions
Isolated cases of necrosis after inadvertent extravascular administration, as well as tumor lysis syndrome and anaphylaxis have been reported.
The risk of developing myelodysplastic syndrome and acute myeloid leukemia is increased in patients treated with alkylating agents (including bendamustine hydrochloride). Secondary malignancies may occur several years after cessation of chemotherapy.
If adverse drug reactions occur, contact your health care provider, pharmacist, or directly to the Adverse Drug Reactions (Actions) Information Database, including reports of drug ineffectiveness
Republican State enterprise on the Right of Economic Management National Center for Expertise of Medicines and Medical Devices of the Committee for Medical and Pharmaceutical Control of the Ministry of Healthcare of the Republic of Kazakhstan
http://www.ndda.kz

Additional information
Composition of the medicinal product
Each vial contains
active substance - bendamustine hydrochloride 100 mg
excipients: mannitol, tertiary butyl alcohol, water for injection.
Description of appearance, smell, taste
Lyophilized powder from white to whitish color, in an amber glass vial.
Reconstituted solution: transparent, almost colorless solution without visible particles.

Release form and packaging
100 mg of the drug is placed in a 20 ml amber glass bottle (type I), sealed with a 20 mm gray bromobutyl stopper and a 20 mm blue cap with a tear-off lining.
1 bottle together with instructions for medical use in Kazakh and Russian are placed in a cardboard box.

Shelf life
2 years
Do not use after the expiration date!

Storage conditions
Store in a dry, dark place at a temperature not exceeding
25 °C.
Keep out of reach of children!

Terms of dispensing from pharmacies
On prescription