Bendamustine-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BENDAMUSTINE-VISTA (BENDAMUSTINE-VISTA)

Composition:

Active substance: bendamustine;

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

Excipient: mannite (E 421);

1 ml of reconstituted concentrate contains 2.5 mg of bendamustine hydrochloride.

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

Main physicochemical properties: white or almost white lyophilized powder.

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

Pharmacological Properties.

Pharmacodynamics.

Bendamustine hydrochloride is an alkylating antineoplastic agent. The antineoplastic and cytotoxic effects of bendamustine hydrochloride are primarily related to the formation of cross-links in single-stranded and double-stranded DNA molecules due to alkylation. As a result, DNA template function, its synthesis, and repair are disrupted.

The antitumor activity of bendamustine hydrochloride has been demonstrated in several in vitro studies on various human tumor cell lines (breast cancer, non-small cell and small cell lung cancer, ovarian carcinoma, and various types of leukemia) and in vivo studies on different experimental models of cancer in animals and humans (melanoma, breast cancer, sarcoma, lymphoma, leukemia, and small cell lung cancer).

Bendamustine hydrochloride exhibits a profile of activity on human tumor cell lines that differs from that of other alkylating agents. The active substance shows either no or only minimal cross-resistance in human tumor cell lines with different resistance mechanisms, at least partially due to its relatively persistent interaction with DNA. Furthermore, bendamustine shows only partial cross-resistance with anthracyclines, alkylating agents, and rituximab. However, the number of analyzed patients is small.

Pharmacokinetics.

Distribution.

The elimination half-life in the beta phase (t1/2ß) after a 30-minute intravenous infusion at a dose of 120 mg/m² body surface area is 28.2 minutes. After a 30-minute intravenous infusion, the central volume of distribution is 19.3 L. At steady state after a bolus intravenous injection, the volume of distribution is 15.8–20.5 L. Over 95% of the active substance is bound to plasma proteins (primarily to albumin).

Metabolism.

The primary route of bendamustine clearance is its hydrolysis, resulting in the formation of monohydroxy- and dihydroxybendamustine. The formation of N-desmethylbendamustine and gamma-hydroxy-bendamustine in the liver involves the cytochrome P450 isoenzyme (CYP) 1A2. Another major metabolic pathway of bendamustine is conjugation with glutathione.

In vitro studies have shown that bendamustine does not inhibit the CYP 1A2, CYP 2C9/10, CYP 2D6, CYP 2E1, or CYP 3A4 enzymes.

Excretion.

The mean total clearance after a 30-minute intravenous infusion at a dose of 120 mg/m² body surface area is 639.4 mL/min. Approximately 20% of the administered dose is excreted in urine within 24 hours. The unchanged bendamustine and its metabolites excreted in urine are ranked in decreasing order of quantity as follows: monohydroxybendamustine > bendamustine > dihydroxybendamustine > oxidized metabolite > N-desmethylbendamustine. Polar metabolites are predominantly excreted via bile.

Hepatic impairment.

In patients with 30–70% tumor involvement of the liver and mild hepatic impairment (serum bilirubin level <1.2 mg/dL), the pharmacokinetic behavior of the drug is not altered. Compared to patients with normal liver and kidney function, no significant differences were observed in Cmax (maximum plasma concentration), tmax (time to reach maximum concentration), AUC (area under the concentration-time curve), t1/2ß (elimination half-life in the beta phase), volume of distribution, or clearance.

AUC and total clearance of bendamustine are inversely proportional to serum bilirubin levels.

Renal impairment.

Compared to patients with normal liver and kidney function, no significant differences in Cmax, tmax, AUC, t1/2ß, volume of distribution, or clearance were observed in patients with creatinine clearance >10 mL/min (including patients undergoing dialysis).

Geriatric patients.

Patients up to 84 years of age participated in pharmacokinetic studies. Age does not appear to influence the pharmacokinetics of bendamustine.

Clinical characteristics.

Indications.

First-line therapy for chronic lymphocytic leukemia (stage B or C according to Binet classification), when combination chemotherapy including fludarabine is not appropriate.

Monotherapy for indolent non-Hodgkin’s lymphomas with disease progression or within 6 months after treatment with rituximab or rituximab-containing therapy.

First-line therapy in combination with prednisone for multiple myeloma (stage II with progression or stage III according to Durie-Salmon classification) in patients over 65 years of age who are not candidates for autologous stem cell transplantation and who have clinical neuropathy at diagnosis that precludes the use of thalidomide or bortezomib.

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 10^9/L and/or platelet count <75 x 10^9/L);
• Surgical intervention less than 30 days prior to initiation of treatment;
• Infections, particularly those associated with leukopenia;
• Vaccination against yellow fever.

Special safety precautions.

When handling Bendamustin-Vista, inhalation and contact with skin or mucous membranes should be avoided (gloves and protective clothing must be used). Contaminated areas of the body should be thoroughly washed with soap and water; eyes should be rinsed with physiological saline solution. Handling should preferably be performed at specialized safety workstations (with laminar airflow). Pregnant women must not be involved in handling cytostatic agents.

Interaction with other medicinal products and other forms of interaction.

In vivo interaction studies have not been conducted.

When bendamustine hydrochloride is used in combination with myelosuppressive agents, the effects of bendamustine hydrochloride and/or concurrently administered myelosuppressive drugs may be potentiated. Any therapy that worsens the patient’s general condition or suppresses bone marrow function may enhance the toxicity of bendamustine hydrochloride.

Combination of bendamustine hydrochloride with cyclosporine or tacrolimus may result in excessive immunosuppression with risk of lymphoproliferative disorders.

Cytostatic agents may impair antibody production following live viral vaccination and increase the risk of infection, which may lead to fatal outcomes. The risk is increased in patients whose immune system is already compromised due to underlying disease.

Bendamustine metabolism involves cytochrome P450 (CYP) 1A2 isoenzyme. Therefore, potential interactions with CYP1A2 inhibitors such as fluvoxamine, ciprofloxacin, acyclovir, and cimetidine are possible.

Drug interaction studies have been conducted only in adult patients.

Special precautions.

Myelosuppression.

Myelosuppression may develop in patients receiving bendamustine hydrochloride. Therefore, white blood cell count, platelets, hemoglobin, and neutrophil levels should be monitored at least once weekly. Before starting the next treatment cycle, the following parameters are recommended: white blood cell count and/or platelet count >4000/μL or >100000/μL, respectively.

Infections.

There have been reports of severe, including fatal, infections associated with the use of bendamustine hydrochloride, including bacterial infections (pneumonia and sepsis), and opportunistic infections caused by organisms such as Pneumocystis jirovecii, varicella-zoster virus, and cytomegalovirus.

Cases of progressive multifocal leukoencephalopathy (PML), including fatal cases, have been reported following treatment with bendamustine, 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. If PML is suspected, 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 lymphopenia and low CD4-positive T-cell counts due to bendamustine use are more susceptible to (opportunistic) infections. Prophylaxis for Pneumocystis jirovecii pneumonia should be considered in patients with low CD4-positive T-cell counts (<200/μL).

Therefore, patients should be monitored for symptoms of respiratory impairment during treatment. Patients who develop signs of infection, such as fever or respiratory symptoms, after treatment with bendamustine hydrochloride, particularly those with myelosuppression, should contact their physician. If signs of (opportunistic) infections occur, discontinuation of bendamustine hydrochloride therapy should be considered.

Hepatitis B reactivation.

Reactivation of hepatitis B virus has been reported in patients with chronic hepatitis B infection following treatment with bendamustine hydrochloride. In some cases, acute liver failure, including fatal outcomes, has occurred. Before initiating treatment with bendamustine hydrochloride, 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 (hepatologist). HBV carriers requiring treatment with bendamustine hydrochloride should be closely monitored for signs of active HBV infection throughout the treatment course and for several months after therapy completion.

Skin reactions.

Skin reactions, including rash, severe skin reactions, and bullous exanthema, have been reported. Some reactions occurred during combination therapy with bendamustine hydrochloride and other antineoplastic agents, although a direct causal relationship has not been established. Cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) have been reported with the use of bendamustine hydrochloride, sometimes with fatal outcomes. Skin reactions may progress, and their severity may increase with further treatment.

The prescribing physician should inform patients about the signs and symptoms of these skin reactions and instruct them to seek immediate medical attention if such symptoms develop.

If skin reactions worsen, administration of Bendamustine-Vista should be temporarily discontinued. If severe skin reactions, likely related to bendamustine hydrochloride, occur, treatment should be discontinued.

Cardiac disorders.

Serum potassium levels should be closely monitored during treatment with bendamustine hydrochloride. If K+ <3.5 mEq/L, potassium supplementation and ECG monitoring should be performed.

Cases of myocardial infarction and heart failure with fatal outcomes have been reported during treatment with bendamustine. Patients with pre-existing cardiac disease or history of cardiac disorders should be under close medical supervision.

Nausea, vomiting.

Anti-emetic agents may be prescribed for symptomatic management of nausea and vomiting.

Tumor lysis syndrome.

Tumor lysis syndrome has been reported in clinical studies associated with treatment using bendamustine hydrochloride. It typically occurs within 48 hours after the first dose of bendamustine hydrochloride and, if untreated, may lead to acute renal failure and death. Preventive measures include careful monitoring of hydration status and biochemical blood parameters, particularly potassium and uric acid levels. Hypouricemic agents (allopurinol and rasburicase) may be considered. Additionally, several cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported when bendamustine hydrochloride was used concomitantly with allopurinol.

Anaphylaxis.

Infusion-related reactions to bendamustine hydrochloride have frequently occurred during clinical studies. Symptoms are usually mild and include fever, chills, pruritus, and skin rash. Anaphylactic and anaphylactoid reactions have occurred rarely. After the first treatment cycle, patients should be questioned about symptoms suggestive of infusion reactions. For patients who experience infusion reactions, preventive measures such as administration of antihistamines, antipyretics, and corticosteroids should be considered to prevent severe reactions.

Re-administration of the drug is not recommended in patients who have experienced grade III or higher allergic-type reactions.

Extravasation.

In case of accidental extravasation, the infusion should be stopped immediately. Before removing the needle, aspirate any drug that has leaked into surrounding tissues. The affected area should then be cooled. The limb should be kept elevated. Additional treatments, such as corticosteroids, do not provide significant benefit.

Non-melanoma skin cancer.

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

Use during pregnancy or breastfeeding.

Pregnancy.

Data on the use of bendamustine hydrochloride in pregnant women are limited. Preclinical studies have shown that bendamustine hydrochloride has embryotoxic/fetotoxic, teratogenic, and genotoxic effects. Bendamustine-Vista should be used during pregnancy only if clearly necessary. Women should be informed of the potential risk to the fetus. If treatment with bendamustine hydrochloride is essential during pregnancy or if pregnancy occurs during treatment, the patient should be informed of the potential risk to the fetus, and close monitoring should be performed. Genetic counseling should be considered.

Contraception.

Bendamustine hydrochloride has teratogenic and mutagenic effects. Effective contraception methods are recommended before and during treatment. Male patients are advised to avoid fathering a child during therapy and for 6 months after drug administration. Due to the potential risk of irreversible infertility, sperm cryopreservation is recommended before starting treatment with bendamustine hydrochloride.

Breastfeeding.

It is unknown whether bendamustine hydrochloride passes into breast milk. Bendamustine-Vista is contraindicated during breastfeeding. Breastfeeding must be discontinued during treatment with Bendamustine-Vista.

Ability to affect driving and operating machinery.

Bendamustine hydrochloride has a significant influence on the ability to drive or operate machinery. During treatment with bendamustine hydrochloride, adverse events such as impaired coordination, peripheral neuropathy, and somnolence have been reported (see section "Adverse reactions"). Patients should be advised to avoid potentially hazardous activities such as driving a car or operating machinery if these symptoms occur.

Administration and Dosage

The solution should be administered by intravenous infusion over 30–60 minutes.

Vials are intended for single use only.

Infusion must be performed under the supervision of a physician qualified and experienced in the use of chemotherapeutic agents.

Bone marrow dysfunction is associated with increased hematological toxicity caused by chemotherapy. Treatment must not be initiated if leukocyte and/or platelet counts are below 3,000/μL or below 75,000/μL, respectively.

Monotherapy for chronic lymphocytic leukemia.

100 mg of bendamustine hydrochloride per 1 m² of body surface area on Day 1 and Day 2; every 4 weeks for up to 6 cycles.

Monotherapy for rituximab-refractory indolent non-Hodgkin’s lymphomas.

120 mg of bendamustine hydrochloride per 1 m² of body surface area on Day 1 and Day 2; every 3 weeks for at least 6 cycles.

Multiple myeloma.

120–150 mg of bendamustine hydrochloride per 1 m² of body surface area on Day 1 and Day 2, and 60 mg of prednisone per 1 m² of body surface area administered intravenously or orally from Day 1 to Day 4; every 4 weeks for at least 3 cycles.

Treatment should be discontinued or delayed if leukocyte and/or platelet counts fall below 3,000/μL or 75,000/μL, respectively. Treatment may be resumed once leukocyte counts rise above 4,000/μL and platelet counts above 100,000/μL.

The nadir of leukocyte and platelet counts typically occurs 14–20 days after administration, with recovery occurring within 3–5 weeks. Regular monitoring of blood counts is recommended during treatment intervals.

In the case of non-hematological toxicity, dose reduction should be based on the most severe grade of overall toxicity in the previous cycle. If Grade III toxicity is observed, a 50% dose reduction is recommended; if Grade IV toxicity occurs, treatment should be discontinued.

If dose adjustment is required, the individually calculated reduced dose should be administered on Day 1 and Day 2 of the treatment cycle.

Special patient groups.

Hepatic impairment.

According to pharmacokinetic data, no dose adjustment is required for patients with mild hepatic impairment (serum bilirubin level <1.2 mg/dL). For patients with moderate hepatic impairment (serum bilirubin level 1.2–3.0 mg/dL), a 30% dose reduction is recommended.

There are no data available for patients with severe hepatic impairment (serum bilirubin level exceeding 3.0 mg/dL).

Renal impairment.

According to pharmacokinetic data, no dose adjustment is required for patients with a creatinine clearance >10 mL/min. Experience with treatment in patients with severe renal impairment is limited.

Elderly patients.

There is no evidence to suggest that elderly patients require dose adjustment.

Instructions for preparing the infusion solution.

When preparing the solution, healthcare personnel must protect their respiratory tract, skin, and mucous membranes (by wearing 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. It is recommended, whenever possible, to use disposable protective equipment with a waterproof absorbent surface. Pregnant women should not handle cytostatic drugs.

Aseptic techniques must be used.

The lyophilized powder for concentrate for infusion solution should be reconstituted with water for injections and diluted with 9 mg/mL (0.9%) sodium chloride injection solution before intravenous infusion. The medicinal product should be used immediately after preparation.

Reconstitution.

Add 10 mL of water for injections to the vial of Bendamustin-Vista containing 25 mg of bendamustine hydrochloride, then shake the vial.

Add 40 mL of water for injections to the vial of Bendamustin-Vista containing 100 mg of bendamustine hydrochloride, then shake the vial.

The reconstituted concentrate contains 2.5 mg of bendamustine hydrochloride per 1 mL and forms a clear, colorless solution.

Dilution.

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

Bendamustin-Vista must be diluted only with 0.9% sodium chloride solution; other injection solutions must not be used.

After reconstitution and dilution, the medicinal product remains physically and chemically stable for 3.5 hours at 25°C and for 2 days at 2–8°C.

Any unused medicinal product or waste materials should be disposed of in accordance with local regulations.

Children.

Bendamustin-Vista must not be used in children due to lack of data on efficacy and safety.

Overdose.

Following a 30-minute infusion of bendamustine hydrochloride once every 3 weeks, the maximum tolerated dose (MTD) was 280 mg/m². Dose-limiting Grade II cardiovascular events according to the Common Terminology Criteria for Adverse Events were observed, accompanied by ischemic changes on ECG.

In one study, a 30-minute infusion of bendamustine hydrochloride on Day 1 and Day 2 every 3 weeks resulted in an MTD of 180 mg/m². Dose-limiting toxicity was Grade IV thrombocytopenia. With this treatment regimen, cardiotoxicity was not dose-limiting.

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

Adverse reactions.

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

The frequency of occurrence is defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), and not known (cannot be estimated from the available data).

BDU – without further specification;

* combination therapy using rituximab.

Description of individual adverse reactions.

There have been individual reports of necrosis following accidental extravascular administration, as well as cases of toxic epidermal necrolysis, tumor lysis syndrome, and anaphylaxis.

The risk of myelodysplastic syndrome and acute myeloid leukemia is increased in patients receiving alkylating agents (including bendamustine). The development of secondary malignancies may occur several years after chemotherapy has been discontinued.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is an important procedure. It allows continuous monitoring of the benefit-risk ratio for the respective medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Incompatibilities.

The medicinal product must not be mixed with other medicinal products except those specified in the section "Administration and dosage".

Shelf life. 3 years.

Storage conditions.

Store in the original packaging in a light-protected place at a temperature not exceeding 25 °C. Keep out of reach and sight of children.

Packaging.

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

Prescription status. Prescription only.

Manufacturer.

Sindan Pharma S.R.L.

Manufacturer's address and location of operations.

Bd. Ion Mihalache, No. 11, Sector 1, 011171, Bucharest, Romania.