Bendamustine axios

INSTRUCTION
for medical use of medicinal product

BENDAMUSTIN AXIOS
(BENDAMUSTIN AXIOS)

Composition:

Active substance: bendamustine hydrochloride;

1 vial contains 25.0 mg or 100.0 mg of bendamustine hydrochloride;

Excipient: mannitol (E 421).

Pharmaceutical form. Powder for concentrate for solution for infusion.

Main physicochemical properties: lyophilized powder from white to almost white in color.

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 effect of bendamustine hydrochloride is primarily associated with the formation of cross-links in single-stranded and double-stranded DNA molecules due to alkylation. As a result, DNA template function and its synthesis 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 various 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 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. In addition, 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 intravenous bolus administration, the volume of distribution is 15.8–20.5 L.

More than 95% of the active substance is bound to plasma proteins (mainly albumin).

Metabolism.

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

In vitro studies have shown that bendamustine does not inhibit the enzymes CYP1A4, CYP2C9/10, CYP2D6, CYP2E1, and CYP3A4.

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. Unchanged bendamustine and its metabolites excreted in urine are distributed in decreasing order of quantity as follows: monohydroxybendamustine > bendamustine > dihydroxybendamustine > oxidized metabolite > N-desmethylbendamustine. Bile excretes predominantly polar metabolites.

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 (beta-phase elimination half-life), 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 on dialysis).

Elderly patients.

Patients up to 84 years of age participated in pharmacokinetic studies. Apparently, age does not affect 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 with fludarabine is not suitable.

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

First-line therapy in combination with prednisone for multiple myeloma (stage II with progression or stage III according to Durie-Salmon classification) in patients aged 65 years and older 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;
• Pregnancy, planned pregnancy, breastfeeding period;
• Moderate and severe hepatic impairment (bilirubin level >3.0 mg/dL);
• Jaundice;
• Severe bone marrow suppression and pronounced changes in blood cell counts (leukocyte count <3000/μL and/or platelet count <75,000/μL);
• Surgery less than 30 days before the start of treatment;
• Infections, especially those associated with leukopenia (risk of infection dissemination);
• Yellow fever vaccination;
• Pediatric population.

Safety precautions.

When handling the medicinal product "Bendamustine Axios," avoid inhalation and contact with skin or mucous membranes (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. It is recommended to work in specially designed safe workstations (with laminar airflow). Pregnant women should not be involved in handling cytostatic agents.

Interaction with other medicinal products and other types of interactions.

When bendamustine hydrochloride is used in combination with myelosuppressive agents, the effects of bendamustine hydrochloride and/or concurrently administered agents acting on the bone marrow 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 lead to excessive immunosuppression with a risk of lymphoproliferation.

Cytostatic agents may affect antibody production after live antiviral vaccination and increase the risk of infection, which may be fatal. The risk is increased in patients whose immunity is already compromised by the underlying disease.

The metabolism of bendamustine is associated with the cytochrome P450 (CYP) 1A2 isoenzyme. Therefore, there is a potential for interaction with CYP1A2 inhibitors, such as fluvoxamine, ciprofloxacin, acyclovir, and cimetidine.

Special considerations for use.

Myelosuppression.

Myelosuppression may develop in patients taking bendamustine hydrochloride. Therefore, leukocyte count, platelet count, hemoglobin, and neutrophil count should be monitored at least once a week. Recommended values before starting the next treatment cycle are: leukocyte count and/or platelet count >4000/μL or >100,000/μL, respectively.

Infections.

There have been reports of infections with serious, including fatal, outcomes, including bacterial infections (pneumonia and sepsis), infections caused by opportunistic microorganisms (e.g., Pneumocystis pneumonia, varicella), and cytomegalovirus. Rarely, infections were associated with hospitalization, septic shock, and fatal outcomes. Patients treated with bendamustine hydrochloride are more susceptible to infections, particularly if they have neutropenia and/or lymphopenia. Treatment with bendamustine hydrochloride may lead to prolonged lymphopenia (<600/μL) and reduced levels of CD4-positive T-cells (T-helpers) (<200/μL) for at least 7–9 months after completion of treatment. Lymphopenia and reduced 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. Therefore, patients should monitor for respiratory symptoms during treatment. Patients with myelosuppression after treatment with bendamustine hydrochloride should consult a physician if they develop signs of infection, including fever or respiratory symptoms.

If signs of (opportunistic) infections are present, 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 following treatment with bendamustine hydrochloride. In some cases, acute liver failure, including fatal outcomes, occurred. Therefore, appropriate preventive measures should be taken before initiating bendamustine therapy to prevent hepatitis B: liver function should be monitored periodically and hepatitis B markers should be tested; appropriate treatment and/or prophylactic therapy should be administered.

Before starting treatment with bendamustine hydrochloride, patients should be tested for HBV infection. Patients with positive hepatitis B test results (including those with active disease) and patients with positive HBV infection test results 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 treatment ends.

Skin reactions.

There have been reports of skin reactions: rash, toxic skin reactions, and bullous exanthema. Some reactions occurred when bendamustine hydrochloride was used in combination with other antineoplastic agents, although a direct link has not been established. 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 with fatal outcomes. Skin reactions may progress, and their severity may increase with further treatment. If skin reactions worsen, administration of "Bendamustine Axios" should be temporarily discontinued. If severe skin reactions, likely related to bendamustine hydrochloride use, occur, treatment should be discontinued.

Cardiac disorders.

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

Myocardial infarction and heart failure with fatal outcomes have been reported during treatment with bendamustine. Patients with cardiac diseases or a history of cardiac disease should be under close medical supervision.

Nausea, vomiting.

Antiemetic agents may be prescribed for symptomatic treatment of nausea and vomiting.

Tumor lysis syndrome.

Tumor lysis syndrome associated with treatment with bendamustine hydrochloride has been reported in clinical studies. It usually occurs within 48 hours after the first dose of bendamustine hydrochloride and, if not treated, may lead to acute renal failure and fatal outcomes. Preventive measures include careful monitoring of hydration status and biochemical blood tests, particularly potassium and uric acid levels. Hypouricemic agents (allopurinol and rasburicase) may be considered during the first 1–2 weeks of treatment with bendamustine hydrochloride, although this is not considered mandatory. Additionally, several cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with concomitant use of bendamustine hydrochloride and allopurinol.

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

Anaphylaxis.

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

Re-administration of the medicinal product is not recommended in patients who experienced grade III or higher allergic reactions.

Extravasation.

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

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 Axios" may be used during pregnancy only if absolutely necessary. The woman should be informed of the risk to the unborn child. If treatment with bendamustine hydrochloride during pregnancy is absolutely necessary or if pregnancy occurs during treatment, the patient should be informed of the risk to the unborn child and continuous monitoring should be performed. Genetic counseling should be considered.

Contraception.

Bendamustine hydrochloride has teratogenic and mutagenic effects. Effective contraceptive methods should be used before and during treatment. Male patients are advised to avoid conception during therapy and for 6 months after administration of the medicinal product. Due to the potential for irreversible infertility, sperm cryopreservation is recommended before starting treatment with bendamustine hydrochloride.

Breastfeeding.

It is unknown whether bendamustine hydrochloride passes into breast milk. "Bendamustine Axios" is contraindicated during breastfeeding; therefore, breastfeeding should be discontinued during treatment.

Ability to affect reaction speed when driving or operating machinery.

Bendamustine hydrochloride has a significant effect on the ability to drive and operate machinery. During treatment with bendamustine hydrochloride, impaired coordination, peripheral neuropathy, and somnolence have been reported. Patients should be advised to avoid potentially hazardous activities, such as driving or operating machinery, if these symptoms occur.

Method of administration and dosage.

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

Vials are for single use only.

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

Impaired bone marrow function is associated with increased hematological toxicity caused by chemotherapy. Treatment should not be initiated if leukocyte and/or platelet counts are <3000/μL or <75,000/μL, respectively.

Monotherapy for chronic lymphocytic leukemia.

100 mg of bendamustine hydrochloride per 1 m² body surface area on days 1 and 2 every 4 weeks.

Monotherapy for indolent non-Hodgkin's lymphomas poorly responsive to rituximab.

120 mg of bendamustine hydrochloride per 1 m² body surface area on days 1 and 2 every 3 weeks.

Multiple myeloma.

120–150 mg of bendamustine hydrochloride per 1 m² body surface area on days 1 and 2, 60 mg of prednisone per 1 m² body surface area intravenously or orally on days 1–4 every 4 weeks.

Treatment should be discontinued if leukocyte and/or platelet counts fall below 3000/μL or 75,000/μL, respectively. Treatment may be resumed after leukocyte count increases to >4000/μL and platelet count to >100,000/μL.

Maximum reduction in leukocyte and platelet counts occurs 14–20 days after administration, with recovery occurring within 3–5 weeks. Continuous monitoring of blood cell counts is recommended during treatment intervals.

In 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 is observed, treatment should be interrupted.

If a patient requires dose adjustment, the individually calculated reduced dose should be administered on days 1 and 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.

No data are available for patients with severe hepatic impairment (serum bilirubin level >3.0 mg/dL).

Renal impairment.

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

Elderly patients.

There is no reason to believe that elderly patients require dose adjustment.

Recommendations for preparation of infusion solution.

When preparing the solution, healthcare personnel must protect their respiratory organs, skin, and mucous membranes (wear gloves and protective clothing). If the medicinal product comes into contact with skin or mucous membranes, wash thoroughly with soap and water; if it gets into the eyes, rinse with physiological saline. If possible, disposable protective equipment with a waterproof absorbent surface is recommended. Pregnant women should not handle cytostatic agents.

Aseptic techniques must be used.

The powder for concentrate for infusion solution should be dissolved in water for injection, diluted with 9 mg/mL (0.9%) sodium chloride injection solution, and then administered by intravenous infusion. The medicinal product should be used immediately after preparation.

Reconstitution.

Add 10 mL of water for injection to the vial of "Bendamustine Axios" containing 25 mg of bendamustine hydrochloride, then shake the vial.

Add 40 mL of water for injection to the vial of "Bendamustine Axios" 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 "Bendamustine Axios" should be diluted with 0.9% sodium chloride solution, with the final volume of the solution being approximately 500 mL.

"Bendamustine Axios" should be dissolved only in 0.9% sodium chloride solution; other injection solutions should not be used.

The medicinal product should not be used if any visible signs of damage or defects in the vial are observed. After dissolution and dilution, the preparation should be visually inspected for the presence of particulate matter or discoloration. The solution may be used only if it is clear and free of foreign particles.

Unused medicinal product or waste/materials should be disposed of according to local regulations.

Children.

"Bendamustine Axios" should not be used in children due to lack of data on efficacy and safety of use.

Overdose.

Symptoms. Since the dose-limiting adverse effect of bendamustine hydrochloride is usually myelosuppression, the predominant manifestations after overdose are likely to be hematological adverse effects associated with leukopenia, thrombocytopenia, and anemia. After overdose, an increased frequency and severity of non-hematological adverse effects observed after bolus administration at therapeutic doses may be expected.

Non-hematological adverse effects that may occur after overdose include: nausea, vomiting, diarrhea, dry mouth, taste alteration, cardiac arrhythmias, skin reactions, stomatitis, neuropathy, central nervous system (CNS) reactions, elevated renal and liver function tests, lung function disorders, alopecia, local irritation, and thrombophlebitis.

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

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

Treatment. There is no specific antidote. Bone marrow transplantation, transfusion therapy (platelets, packed red blood cells), or hematopoietic growth factors may be required 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).

Frequency of occurrence is defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), and not known (cannot be determined from available data).

Description of individual adverse reactions.

There have been reports of several cases of Stevens-Johnson syndrome and toxic epidermal necrolysis in patients receiving bendamustine in combination with allopurinol or in combination with allopurinol and rituximab.

Isolated reports have been received regarding urticaria; local irritation and thrombophlebitis; soft tissue necrosis following accidental extravascular administration of the drug; pancytopenia; reactivation of hepatitis B virus; tumor lysis syndrome; and anaphylaxis.

A decrease in the CD4/CD8 ratio may occur. A reduction in lymphocyte count has been observed. In patients with compromised immunity, the risk of infection (e.g., herpes zoster) may increase.

There have been isolated reports of necrosis following accidental extravascular administration, as well as the occurrence 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). Secondary malignancies may develop several years after chemotherapy has been discontinued.

Reporting of adverse reactions.

Reporting of adverse reactions after drug registration is of great importance. This enables ongoing monitoring of the benefit-risk balance of the drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua/.

Shelf life.

3 years.

Reconstitution

The powder should be reconstituted immediately after opening the vial.

The reconstituted concentrate must be immediately diluted with 0.9% sodium chloride solution for injection.

Infusion solution

After reconstitution and dilution, chemical and physical stability has been demonstrated for 3.5 hours at 25 °C under normal lighting conditions and for 2 days at 2 °C to 8 °C in polyethylene bags protected from light.

From a microbiological standpoint, the product should be used immediately. If not used immediately, the duration and conditions of storage are the responsibility of the user and should generally not exceed 24 hours at 2 °C to 8 °C, unless reconstitution/dilution was performed under strictly aseptic conditions.

Storage conditions.

Does not require special storage conditions.

Keep out of reach of children.

Incompatibility.

This medicinal product must not be mixed with other medicinal products except those specified in the section "Instructions for use and dosage".

Packaging.

25 mg in a glass vial, 1, 5, 10 or 20 vials per cardboard pack.

100 mg in a glass vial, 1 or 5 vials per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

АксіоНово ГмбХ/

AxioNovo GmbH.

Manufacturer's address and place of business.

Kammerichstrasse 39, 33647 Bielefeld, Germany/

Kammerichstrasse 39, 33647 Bielefeld, Germany.