Bendamusvista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BENDAMUSVISTA (BENDAMUSVISTA)

Composition:

Active substance: bendamustine;

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

Excipient: mannitol (E 421).

Pharmaceutical form. Powder for concentrate for solution for infusion.

Main physicochemical properties: white, microcrystalline powder.

Pharmacotherapeutic group. Antineoplastic agent, alkylating compound. ATC code: L01A A09.

Pharmacological properties.

Pharmacodynamics.

Bendamustine hydrochloride is an alkylating antineoplastic agent with bifunctional alkylating activity. The antineoplastic and cytotoxic effects of bendamustine hydrochloride are primarily related to the formation of interstrand cross-links in single- and double-stranded DNA due to alkylation. As a result, DNA template function and DNA synthesis are disrupted. The antineoplastic activity of bendamustine hydrochloride has been confirmed in numerous in vitro studies on various tumor cell lines (breast cancer, non-small cell and small cell lung cancer, ovarian cancer, and various types of leukemia) and in vivo on various experimental animal and human tumor models (melanoma, breast cancer, sarcoma, lymphoma, leukemia, and small cell lung cancer). The activity profile of bendamustine hydrochloride demonstrated in human tumor cells differs from that of other alkylating agents. Bendamustine hydrochloride shows no or only minimal cross-resistance in human tumor cell lines with different resistance mechanisms, which is at least partially explained by its longer-lasting interaction with DNA compared to other alkylating agents. Furthermore, clinical studies have shown that there is no complete cross-resistance between bendamustine and anthracyclines, alkylating agents, or rituximab. A small number of patients were evaluated.

Pharmacokinetics.

Distribution.

The half-life (t_1/2) in the first phase after a 30-minute intravenous infusion of bendamustine at a dose of 120 mg/m² body surface area was 28.2 minutes. After a 30-minute intravenous infusion, the central volume of distribution was 19.3 L. Following intravenous bolus administration, the volume of distribution at steady state ranged from 15.8 to 20.5 L.

Over 95% of the active substance is bound to plasma proteins (primarily albumin).

Metabolism.

Bendamustine hydrochloride is primarily metabolized in the liver. The main route of elimination of bendamustine hydrochloride from the body is hydrolysis, resulting in the formation of monohydroxy- and dihydroxybendamustine. The formation of N-desmethylbendamustine and the gamma-hydroxybendamustine metabolite in the liver involves the cytochrome P450 isoenzyme CYP1A2. Other significant metabolic pathways of bendamustine include conjugation with glutathione. In vitro, bendamustine does not inhibit CYP1A4, CYP2C9/10, CYP2D6, CYP2E1, or CYP3A4.

Excretion.

The mean total clearance after a 30-minute intravenous infusion of the drug at a dose of 120 mg/m² in 12 subjects was 639.4 mL/min. Approximately 20% of the administered dose was excreted in urine within 24 hours.

Unchanged bendamustine and its metabolites excreted in urine are ranked in decreasing order of quantity as follows: monohydroxybendamustine > bendamustine > dihydroxybendamustine > oxidized metabolite > N-desmethylbendamustine. Biliary excretion consists predominantly of polar metabolites.

Pharmacokinetics in hepatic impairment.

In patients with 30–70% tumor/metastatic involvement of the liver and mild impairment of hepatic function (serum bilirubin < 1.2 mg/dL), no significant differences were observed compared to patients with normal hepatic and renal function in the following parameters: maximum plasma concentration of bendamustine (C_max), time to reach maximum concentration (t_max), area under the plasma concentration-time curve (AUC), beta-phase elimination half-life (t_1/2β), volume of distribution, clearance, and excretion. However, AUC and total systemic clearance of bendamustine are inversely correlated with serum bilirubin levels.

Pharmacokinetics in renal impairment.

In patients with creatinine clearance > 10 mL/min (including patients on dialysis), no significant differences were observed compared to patients with normal hepatic and renal function in the following parameters: C_max, t_max, AUC, t_1/2β, volume of distribution, and excretion.

Elderly patients.

Patients up to 84 years of age participated in pharmacokinetic studies. Age does not have a significant effect on the pharmacokinetics of bendamustine hydrochloride.

Clinical Characteristics.

Indications.

• First-line therapy for chronic lymphocytic leukemia (Binet stage B and C), when combination therapy including fludarabine is not suitable.
• Monotherapy for indolent non-Hodgkin's lymphomas with disease progression during or within 6 months after treatment with rituximab or rituximab-containing regimens.
• First-line therapy in combination with prednisone for multiple myeloma (Durie-Salmon stage II with progression or stage III) in patients aged 65 years and older, for whom stem cell transplantation is not suitable and who have clinical neuropathy at diagnosis, when thalidomide or bortezomib are not suitable for use.

Contraindications.

Hypersensitivity to bendamustine hydrochloride and/or mannitol; breastfeeding period; severe hepatic impairment (bilirubin level > 3.0 mg/dL); jaundice; severe bone marrow suppression and marked changes in blood cell counts (leukocyte count < 3 x 10⁹/L and/or platelet count < 75 x 10⁹/L); surgical intervention within less than 30 days prior to initiation of treatment; infections, particularly those associated with leukopenia; period of vaccination against yellow fever.

Interaction with other medicinal products and other forms of interaction.

No in vivo studies have been conducted. When BendamusVista is administered concomitantly with myelosuppressive agents, the effects of drugs affecting bone marrow function may be potentiated. Any treatment that weakens the general condition of the patient or suppresses bone marrow function may enhance the toxic effects of BendamusVista. Concomitant administration of BendamusVista with cyclosporine or tacrolimus may result in profound immunosuppression with risk of lymphoproliferative disorders. Cytostatic agents may reduce antibody production following vaccination with live vaccines and increase the risk of infection, which may lead to fatal outcomes. The risk is increased in patients with impaired immune systems due to underlying disease. Bendamustine is metabolized by the CYP1A2 isoenzyme of cytochrome P450 (see section "Pharmacokinetics"). Therefore, a potential interaction exists with CYP1A2 inhibitors such as fluvoxamine, ciprofloxacin, acyclovir, and cimetidine.

Children

Interaction studies have been conducted only in adults.

Special precautions for use.

Myelosuppression.

Myelosuppression may occur in patients receiving bendamustine; therefore, monitoring of white blood cell count, platelets, hemoglobin, and neutrophils should be performed at least once weekly. Treatment with BendamusVista may be continued if the following laboratory values are met: leukocytes > 4×10⁹/L and platelets > 100×10⁹/L.

Infections.

Serious infections, including fatal cases, have been reported, such as bacterial infections (pneumonia and sepsis) and opportunistic infections caused by opportunistic microorganisms, including Pneumocystis jirovecii pneumonia, varicella, and cytomegalovirus. Infections have occasionally led to hospitalization, septic shock, and death. Patients with neutropenia and/or leukopenia induced by bendamustine are more susceptible to developing infections. Cases of progressive multifocal leukoencephalopathy (PML), including fatal cases, have been reported following bendamustine use, primarily in combination with rituximab or obinutuzumab. PML should be considered in the differential diagnosis of patients presenting with new or worsening neurological, cognitive, or behavioral signs or symptoms. In suspected cases of PML, appropriate diagnostic investigations should be performed and treatment discontinued until PML is ruled out.

Treatment with bendamustine hydrochloride may result in prolonged lymphopenia (< 600/μL) and reduced levels of CD4-positive T-cells (T-helper cells) (< 200/μL) for at least 7–9 months after completion of therapy. Lymphopenia and decreased CD4-positive T-cell counts are more pronounced when bendamustine is used in combination with rituximab. Patients with leukopenia and low CD4-positive T-cell counts due to bendamustine use are more susceptible to (opportunistic) infections. Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) should be considered in patients with low CD4-positive T-cell counts (<200/μL). Patients should be advised to monitor for symptoms of respiratory impairment during treatment. Patients who develop myelosuppression due to bendamustine hydrochloride should seek medical attention if signs of infection occur, particularly fever or respiratory symptoms. If signs of (opportunistic) infections are present, discontinuation of bendamustine hydrochloride therapy should be considered.

Reactivation of herpes virus may occur.

Progressive multifocal leukoencephalopathy (PML) should be considered as an important diagnostic consideration in patients with new or worsening neurological, cognitive, or behavioral signs/symptoms. If PML is suspected, appropriate diagnostic evaluations should be performed and treatment suspended until PML is excluded.

Hepatitis B reactivation.

Reactivation of hepatitis B virus has been reported in patients who are chronic carriers of HBV following administration of bendamustine hydrochloride. In some cases, acute liver failure, including fatal outcomes, has occurred. Therefore, appropriate preventive measures should be taken prior to initiating bendamustine therapy to prevent hepatitis B reactivation: patients should be tested for HBV infection. Patients with positive test results for hepatitis B (including those with active disease) and patients who test positive for HBV infection during treatment should consult a physician (a hepatologist). HBV carriers requiring treatment with bendamustine hydrochloride should be closely monitored for symptoms of active HBV infection throughout the treatment course and for several months after therapy ends.

Skin reactions.

Skin reactions, including rash, toxic skin reactions, and bullous exanthema, have been reported. Cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) have been reported with the use of bendamustine hydrochloride, sometimes resulting in death. Physicians prescribing bendamustine should inform patients about the signs and symptoms of these reactions and advise immediate medical attention if they occur.

Some reactions occurred when bendamustine hydrochloride was used in combination with other antineoplastic agents, so a definitive causal relationship cannot always be established. Skin reactions may progress with continued treatment and their manifestations may intensify. If skin reactions progress, administration of bendamustine should be withheld. In cases of severe skin reactions where a causal relationship with bendamustine is suspected, the drug should be discontinued.

Cardiac disorders.

Serum potassium levels should be monitored during treatment with the medicinal product, and potassium supplements should be administered if serum potassium is ≤3.5 mmol/L. Electrocardiographic monitoring is also recommended.

Cases of myocardial infarction and heart failure, including fatal outcomes, have been reported during treatment with bendamustine. Patients with pre-existing cardiac disease or a history of cardiac disorders should be closely monitored.

Nausea, vomiting.

Antiemetic medications should be used for symptomatic management of nausea and vomiting.

Tumor lysis syndrome.

Tumor lysis syndrome has been reported in clinical studies. It typically occurs within 48 hours after the first dose and, if untreated, may lead to acute renal failure and death. Preventive measures include adequate hydration, monitoring of biochemical parameters, particularly potassium and uric acid levels. During the first 2 weeks of therapy with BendamusVista, the use of hypouricemic agents (allopurinol or rasburicase) may be considered. However, several cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported when bendamustine was used concomitantly with allopurinol.

Anaphylaxis.

Infusion reactions to bendamustine have frequently occurred in clinical trials. Symptoms are usually mild and include fever, chills, pruritus, and rash. Severe anaphylactic and anaphylactoid reactions occur rarely. After the first treatment cycle, patients should be questioned about any history of infusion reaction symptoms. For patients who have previously experienced infusion reactions, preventive measures, including premedication with antihistamines, antipyretics, and corticosteroids, should be considered. Re-administration of the drug is not recommended for patients who have experienced grade III or higher allergic reactions.

Contraception.

Bendamustine hydrochloride has teratogenic and mutagenic effects. Women should use effective contraceptive methods to prevent pregnancy during treatment with BendamusVista. Male patients are advised to use effective contraception during therapy and for 6 months after the last dose. Sperm cryopreservation should be considered before starting bendamustine hydrochloride therapy due to the risk of irreversible infertility.

Extravasation.

In case of extravasation, the infusion should be immediately stopped. After brief aspiration, the needle should be removed. The site of extravasation should be cooled, and the affected limb elevated. The use of corticosteroids or other supportive treatments has not shown significant benefit.

Secondary malignancies.

There are reports of secondary malignancies, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma. The relationship to bendamustine has not been established.

Non-melanoma skin cancer.

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

Use during pregnancy or breastfeeding.

Pregnancy.

There are insufficient data on the use of BendamusVista during pregnancy. In preclinical studies, bendamustine has shown embryotoxic/fetotoxic, teratogenic, and genotoxic effects. The drug should not be administered during pregnancy except in life-threatening situations. Women should be informed of the potential risk to the fetus. Genetic counseling is required if pregnancy occurs during treatment.

Contraception.

Effective contraceptive methods should be used before and during treatment with bendamustine.

Male patients are advised to avoid fathering a child during therapy and for 6 months after the last dose. Sperm cryopreservation is recommended before starting bendamustine hydrochloride therapy due to the risk of irreversible infertility.

Breastfeeding period.

It is unknown whether bendamustine is excreted in human breast milk; therefore, the use of bendamustine hydrochloride during breastfeeding is contraindicated (see section "Contraindications"). If bendamustine hydrochloride must be used during lactation, breastfeeding must be discontinued.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product BendamusVista has a significant effect on the ability to drive and operate machinery. During treatment with bendamustine, cases of 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.

Method of Administration and Dosage

Intended for intravenous administration over 30–60 minutes.

The medicinal product BendamusVista should be administered only under the supervision of a physician experienced in anticancer therapy. Strict adherence to the instructions for use must be maintained during administration.

Bone marrow suppression is associated with increased hematological toxicity of chemotherapy. Treatment with bendamustine should not be initiated if the white blood cell count is < 3 × 10⁹/L and/or the platelet count is < 75 × 10⁹/L (see section "Contraindications").

Monotherapy for chronic lymphocytic leukemia.
Administer at a dose of 100 mg/m² on days 1 and 2 of the cycle; repeat the cycle every 4 weeks.

Monotherapy for indolent non-Hodgkin's lymphomas refractory to rituximab.
Administer at a dose of 120 mg/m² on days 1 and 2 of the cycle; repeat the cycle every 3 weeks.

Multiple myeloma
Administer at a dose of 120–150 mg/m² on days 1 and 2 of the cycle, or at 60 mg/m² daily on days 1 to 4 of the cycle, in combination with intravenous or oral prednisolone; repeat the cycle every 4 weeks.

Treatment with bendamustine must be discontinued if the white blood cell count falls below 3 × 10⁹/L and/or the platelet count falls below 75 × 10⁹/L. Treatment may be resumed when the white blood cell count increases to > 4 × 10⁹/L and the platelet count to > 100 × 10⁹/L. Decreases in leukocytes, neutrophils, and platelets typically occur on days 14–20, with recovery occurring within 3–5 weeks. Blood parameters should be monitored during therapy (see section "Special Warnings and Precautions for Use"). In cases of non-hematological toxicity, dose reduction should be based on the severity of overall toxicity criteria from the previous treatment cycle. A 50% dose reduction is recommended for grade 3 overall toxicity criteria; treatment should be discontinued for grade 4 overall toxicity criteria.

If dose reduction is required, it should be performed individually on days 1 and 2 of the treatment cycle.

Use in patients with hepatic impairment.
Based on pharmacokinetic data, no dose adjustment is necessary for patients with mild hepatic impairment (serum bilirubin level < 1.2 mg/dL). A 30% dose reduction of the medicinal product is recommended for patients with moderate hepatic impairment (serum bilirubin level 1.2–3 mg/dL). There are no data on the use of the medicinal product in patients with severe hepatic impairment (serum bilirubin level > 3 mg/dL) (see section "Contraindications").

Use in patients with renal impairment.
Based on pharmacokinetic data, no dose adjustment is necessary for patients with creatinine clearance > 10 mL/min. Experience with the use of the medicinal product in patients with severe renal impairment is limited.

Elderly patients
There is no evidence to suggest the need for dose adjustment in elderly patients.

Recommendations for preparation of infusion solution.
During preparation of the solution, healthcare personnel must protect their respiratory tract, skin, and mucous membranes (wear gloves and protective clothing). In case of contact with skin or mucous membranes, wash thoroughly with soap and water; in case of eye contact, rinse with physiological saline solution. Whenever possible, it is recommended to use disposable protective equipment with waterproof absorbent surfaces. Pregnant women should not handle or reconstitute cytostatic agents.

To prepare the solution, the contents of the vial should be dissolved in water for injection as follows:

• Add 10 mL of water for injection to the vial containing 25 mg of bendamustine hydrochloride, then shake the vial.
• Add 40 mL of water for injection to the vial containing 100 mg of bendamustine hydrochloride, then shake the vial.

Immediately after obtaining a clear solution (usually within 5–10 minutes), the total dose should be further diluted with 0.9% sodium chloride solution to a final volume of approximately 500 mL.

The medicinal product should only be diluted with 0.9% sodium chloride solution; other injection solutions must not be used.

Aseptic techniques must be strictly observed.

Children.
The medicinal product BendamusVista is not used in children due to lack of data on efficacy and safety.

Overdose.
The maximum tolerated dose was 280 mg/m² administered as a 30-minute infusion once every 3 weeks.

Symptoms. Cardiac manifestations classified as grade II according to general toxicity criteria included ischemic changes on ECG and were considered dose-limiting.

In a subsequent study using a 30-minute infusion on days 1 and 2 of the cycle every 3 weeks, the maximum tolerated dose was 180 mg/m². Dose-limiting toxicity was grade IV thrombocytopenia. In this regimen, cardiac toxicity was not dose-limiting. Overdose may lead to increased severity of adverse reactions.

Treatment. There is no specific antidote. Management may require bone marrow transplantation, transfusion therapy (platelets, packed red blood cells), or use of hematopoietic growth factors to manage hematological adverse effects. Bendamustine hydrochloride and its metabolites are minimally removed by dialysis.

Adverse Reactions

The most common adverse reactions of bendamustine hydrochloride are hematological adverse reactions (leukopenia, thrombocytopenia), skin toxicity (allergic reactions), constitutional symptoms (fever), and gastrointestinal symptoms (nausea, vomiting).

Adverse reactions are listed according to frequency of occurrence as follows: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from available data).

Infections and infestations:

very common: infections; NOS ,* including opportunistic infections (e.g., herpes zoster, cytomegalovirus, hepatitis B);

uncommon: Pneumocystis pneumonia;

rare: sepsis;

very rare: primary atypical pneumonia.

Benign and malignant neoplasms:

common: tumor lysis syndrome;

uncommon: myelodysplastic syndrome, acute myeloid leukemia.

Blood and lymphatic system disorders:

very common: leukopenia, NOS ,* thrombocytopenia, lymphopenia;

common: bleeding, anemia, neutropenia;

uncommon: pancytopenia;

rare: bone marrow disorders;

very rare: hemolysis.

Immune system disorders:

common: hypersensitivity reactions NOS *;

rare: anaphylactic reaction, anaphylactoid reaction;

very rare: anaphylactic shock.

Nervous system disorders:

very common: headache;

common: insomnia, dizziness;

rare: somnolence, aphonia;

very rare: taste disturbance, paresthesia, peripheral sensory neuropathy, anticholinergic syndrome, neurological disorders, ataxia, encephalitis.

Cardiac disorders:

common: cardiac dysfunction, including palpitations, angina pectoris, arrhythmia;

uncommon: pericardial effusion, myocardial infarction, heart failure;

very rare: tachycardia;

frequency not known: atrial fibrillation.

Vascular disorders:

common: arterial hypotension, arterial hypertension;

rare: acute circulatory (vascular) failure;

very rare: phlebitis.

Respiratory, thoracic and mediastinal disorders:

common: pulmonary dysfunction;

very rare: pulmonary fibrosis;

frequency not known: pneumonitis, pulmonary alveolar hemorrhage.

Gastrointestinal disorders:

very common: nausea, vomiting;

common: diarrhea, constipation, stomatitis;

very rare: hemorrhagic esophagitis, gastrointestinal hemorrhage.

Skin and subcutaneous tissue disorders:

common: alopecia, skin disorders NOS *, urticaria;

frequency not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome*); rare: erythema, dermatitis, pruritus, rash (including maculopapular), hyperhidrosis.

Reproductive system and breast disorders:

common: amenorrhea;

very rare: infertility.

Hepatobiliary disorders:

frequency not known: hepatic failure.

General disorders and administration site conditions:

very common: mucositis, asthenia, pyrexia;

common: pain, fever, dehydration, anorexia;

very rare: multiorgan failure.

Investigations:

very common: decreased hemoglobin, increased creatinine and urea;

common: increased alanine aminotransferase/aspartate aminotransferase activity, alkaline phosphatase, bilirubin levels, hypokalemia.

Renal and urinary disorders:

frequency not known: renal failure.

NOS = not otherwise specified

(*= combination therapy with rituximab).

Several cases of Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported in patients receiving bendamustine hydrochloride in combination with allopurinol and/or rituximab.

Lymphocyte count reduction has been observed. A decreased CD4/CD8 ratio is possible. Patients with immunosuppression may have an increased risk of infections (e.g., herpes zoster).

There have been isolated reports of necrosis, toxic epidermal necrolysis, tumor lysis syndrome, and anaphylaxis following accidental extravascular administration of the drug. Secondary malignancies have been reported, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma. The risk of myelodysplastic syndrome and acute myeloid leukemia is increased in patients receiving alkylating agents (including bendamustine). Development of secondary malignancies may occur several years after chemotherapy has been discontinued. Possible adverse effects include bone marrow function suppression, urticaria, local irritation and thrombophlebitis, soft tissue necrosis following accidental extravascular administration, pancytopenia, headache, dizziness, atrial fibrillation, reactivation of hepatitis B virus.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug registration is important. It allows continuous 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 drug efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life. 3 years.

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

Packaging. 25 mg or 100 mg powder in a vial; 1 vial per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Sicton España, S.L.

and

Sicton s.r.o.

Manufacturer's address and place of business.

Calle C/ Castello, no1, Sant Boi de Llobregat, Barcelona, 08830, Spain

and

Brnenska 32/sr. 597, Blansko, 67801, Czech Republic.