MILANDA 25 SOLUTION FOR INJECTION

Indications

• Multiple myeloma
• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin lymphoma

Dosage

Children: There is limited data on the use of bendamustine in paediatric patients. Refer to the BNF for Children for specific dosing recommendations.

Adults: The recommended adult dosage for bendamustine varies depending on the specific indication and treatment regimen; refer to the BNF for detailed dosing guidelines.

Mechanism of action

Bendamustine acts as a bifunctional alkylating agent that forms electrophilic alkyl groups, which covalently bond to DNA and other cellular macromolecules. This results in the formation of intra- and inter-strand crosslinks between DNA bases, ultimately leading to apoptosis. The exact molecular mode of action remains poorly understood; however, it has been shown to induce apoptosis in myeloma cell lines by activating specific DNA-damage signaling pathways and causing cell cycle arrest.

Pharmacodynamics

Bendamustine has been studied for its impact on cardiac function, with no significant mean changes in QTc interval greater than 20 milliseconds detected within one hour post-infusion. This suggests that the drug does not pose significant risks for QT prolongation in clinical use.

Pharmacokinetics

Bendamustine is administered intravenously, and its pharmacokinetics are characterized by rapid distribution and elimination. It has a half-life of approximately 30 minutes to 2 hours, depending on individual patient factors. Bendamustine is metabolized in the liver, primarily by cytochrome P450 enzymes, and its metabolites are excreted primarily through the urine.

Adverse effects

• Nausea
• Vomiting
• Myelosuppression
• Fatigue
• Fever
• Infections
• Rash
• Peripheral neuropathy

Precautions

• Use with caution in patients with liver or kidney impairment
• Monitor blood counts regularly due to the risk of myelosuppression
• Avoid use in patients with active infections

Pregnancy

Bendamustine may cause fetal harm. It is not recommended for use during pregnancy.

Breast-feeding

It is not known whether bendamustine is excreted in human milk. Caution should be exercised when administering to a nursing woman.

Storage

Store at room temperature, away from light and moisture. Do not freeze.

Formulations

• Injection, 100 mg/4 mL (single-use vial)

Indications

• Chronic lymphocytic leukemia
• Non-Hodgkin's lymphoma
• Multiple myeloma

Dosage

Children: Refer to BNF for Children for specific dosing guidelines.

Adults: Refer to local protocol for specific dosing guidelines.

Mechanism of action

Bendamustine acts as an alkylating agent, resulting in the formation of DNA cross-links which impede DNA replication and transcription. This leads to cell cycle arrest and ultimately triggers apoptosis in rapidly dividing cancer cells. Additionally, it has antimetabolite properties, inhibiting the synthesis of nucleic acids, thus further contributing to its cytotoxic effects.

Pharmacodynamics

The pharmacodynamics of bendamustine involve its dual action on both DNA and RNA synthesis. The drug's ability to induce DNA cross-linking is particularly noteworthy, as it leads to a robust cytotoxic effect in neoplastic cells. Bendamustine also modulates the immune response by affecting the tumor microenvironment, which may enhance its efficacy against certain malignancies.

Pharmacokinetics

Bendamustine is administered via intravenous infusion, and its pharmacokinetics include rapid distribution into tissues with a volume of distribution of approximately 20 L/m². The elimination half-life ranges from 30 to 60 minutes, with metabolites being primarily excreted through the urine. Due to its unique structure, bendamustine does not show significant cross-resistance with other alkylating agents.

Adverse effects

• Gastrointestinal disturbances
• Bone marrow suppression
• Increased risk of infections
• Nausea and vomiting
• Fatigue
• Anemia
• Thrombocytopenia
• Leukopenia

Interactions

• Increased risk of myelosuppression with other myelosuppressive agents
• Potential for increased toxicity with live vaccines
• May interact with anticoagulants

Precautions

• Monitor for signs of infection due to immunosuppression
• Caution in patients with liver impairment
• Avoid in patients with a history of severe hypersensitivity reactions to bendamustine or other alkylating agents
• Patients with known hepatitis B virus infection should be monitored for reactivation

Pregnancy

Bendamustine is not recommended during pregnancy due to potential harm to the fetus. Women of childbearing potential should be advised to use effective contraception.

Breast-feeding

Breastfeeding is not recommended during treatment with bendamustine due to the potential for serious adverse effects in the nursing infant.

Storage

Store in a cool, dry place, away from light. Keep out of reach of children.

Formulations

• Bendamustine hydrochloride injection

Mechanism of action

Bendamustine is a bifunctional mechlorethamine derivative capable of forming electrophilic alkyl groups that covalently bond to other molecules. Through this function as an alkylating agent, bendamustine causes intra- and inter-strand crosslinks between DNA bases resulting in cell death. It is active against both active and quiescent cells, although the exact mechanism of action is unknown. Multiple myeloma is a fatal hematological disease caused by malignant transformation of plasma cells. Bendamustine has been proven to be a potent alternative to melphalan in phase 3 studies, yet its molecular mode of action is still poorly understood. The four-myeloma cell lines NCI-H929, OPM-2, RPMI-8226, and U266 were cultured in vitro. Apoptosis was measured by flow cytometry after annexin V FITC and propidium iodide staining. Cell cycle distribution of cells was determined by DNA staining with propidium iodide. Intracellular levels of (phosphorylated) proteins were determined by western blot. /It was shown/ that bendamustine induces apoptosis with an IC50 of 35-65 mug/ml and with cleavage of caspase 3. Incubation with 10-30 mug/ml results in G2 cell cycle arrest in all four-cell lines. The primary DNA-damage signaling kinases ATM and Chk2, but not ATR and Chk1, are activated. The Chk2 substrate Cdc25A phosphatase is degraded and Cdc2 is inhibited by inhibitory phosphorylation of Tyr15 accompanied by increased cyclin B levels. Additionally, p53 activation occurs as phosphorylation of Ser15, the phosphorylation site for ATM. p53 promotes Cdc2 inhibition by upregulation of p21. Targeting of p38 MAPK by the selective inhibitor SB202190 significantly increases bendamustine induced apoptosis. Additionally, SB202190 completely abrogates G2 cell cycle arrest. Bendamustine induces ATM-Chk2-Cdc2-mediated G2 arrest and p53 mediated apoptosis. Inhibition of p38 MAPK augments apoptosis and abrogates G2 arrest and can be considered as a new therapeutic strategy in combination with bendamustine. Microarray-based gene expression profiling, real-time PCR, immunoblot, cell cycle, and functional DNA damage repair analyses were used to characterize response to bendamustine and compare it with chlorambucil and phosphoramide mustard. Bendamustine displays a distinct pattern of activity unrelated to other DNA-alkylating agents. Its mechanisms of action include activation of DNA-damage stress response and apoptosis, inhibition of mitotic checkpoints, and induction of mitotic catastrophe. In addition, unlike other alkylators, bendamustine activates a base excision DNA repair pathway rather than an alkyltransferase DNA repair mechanism. These results suggest that bendamustine possesses mechanistic features that differentiate it from other alkylating agents and may contribute to its distinct clinical efficacy profile. Bendamustine is a bifunctional mechlorethamine derivative containing a purine-like benzimidazole ring. Mechlorethamine and its derivatives form electrophilic alkyl groups. These groups form covalent bonds with electron-rich nucleophilic moieties, resulting in interstrand DNA crosslinks. The bifunctional covalent linkage can lead to cell death via several pathways. Bendamustine is active against both quiescent and dividing cells. The exact mechanism of action of bendamustine remains unknown.

Pharmacodynamics

No mean changes in QTc interval greater than 20 milliseconds were detected up to one hour post-infusion.