Bendamustine Hydrochloride: A Ray of Hope for Non-Hodgkin Lymphoma Patients

Drug Overview:

Bendamustine hydrochloride is used to treat a type of non-Hodgkin's lymphoma (NHL), a disease that develops in a specific type of white blood cell important for fighting infections. Even though this lymphoma was previously treated with another drug, it is still advancing slowly and has become worse. The United States Food and Drug Administration (FDA) approved Bendamustine for the management of chronic lymphocytic leukemia (CLL) in March 2008 and for indolent B-cell non-Hodgkin lymphoma (NHL) (a slow-growing cancer of white blood cells called lymphocytes) that does not respond to Rituximab treatment in October 2008.

For Patients:

What Is Non-Hodgkin Lymphoma?

Non-Hodgkin lymphoma comprises a collection of blood cancers that typically emerge within the lymphatic system and are characterized as acquired genetic abnormalities. These conditions do not exist from birth but arise when genetic changes or mutations occur within specific cells. In this instance, the affected cells belong to the immune system and are either B lymphocytes (B cells) or T lymphocytes (T cells).

There are over 70 distinct types of non-Hodgkin lymphoma. Advances in medical treatments, including targeted therapies, have extended the lifespan of individuals with these disorders. In certain instances, treatments can completely eradicate all indications and symptoms of non-Hodgkin lymphoma, resulting in a cure. In other cases, the objective of treatment is to achieve remission and maintain it for as long as possible.

What Are the Clinical Indications For Bendamustine Hydrochloride?

Bendamustine injection is employed in the management of chronic lymphocytic leukemia (CLL), which is a form of white blood cell cancer. Additionally, it is utilized for treating a specific type of slow-progressing non-hodgkin's lymphoma (NHL), a type of cancer originating from infection-fighting white blood cells that have persistently worsened despite prior treatment with another medication. Bendamustine belongs to a category of drugs known as alkylating agents and operates by eradicating existing cancer cells while also restraining the development of new ones.

How Should One Use This Medication?

Bendamustine is available as a liquid or as a powder that can be dissolved in a liquid and injected intravenously (IV). A doctor, nurse, or other healthcare provider usually administers this injection at a hospital or outpatient clinic. For a quick infusion, the injection procedure can be completed in ten minutes; for a slower infusion, it can take 30 to 60 minutes. For non-Hodgkin's lymphoma (NHL) therapy, Bendamustine injection is often given once daily for two days; then, there is a 19-day respite from the drug. For up to eight cycles, this treatment cycle may be repeated every 21 days.

If a patient experiences specific adverse effects, the physician may find it necessary to make adjustments to the patient's treatment regimen or modify the prescribed dosage. To mitigate or manage these adverse effects, the physician may also suggest alternative medications. Throughout the course of Bendamustine injection treatment, it remains crucial for the patient to provide regular updates to the physician regarding their well-being and any adverse effects they may be encountering.

What Are the Things to Inform the Doctor Before Taking the Drug?

Here are some important points to keep in mind before receiving a Bendamustine injection:

• Allergies: Before starting Bendamustine treatment, the patient should inform their doctor and pharmacist if they are allergic to Bendamustine, other medications, or any of the ingredients in Bendamustine injection.

• Medications: The patient should let their doctor know about every prescription and over-the-counter drug, vitamin, herbal product, and nutritional supplement they are now taking or intend to take. Specific medications like Ciprofloxacin, Fluvoxamine, and Omeprazole should be mentioned, as they may interact with Bendamustine and require dose adjustments or close monitoring. It is crucial to disclose all medications, even those not mentioned in this list.

• Medical History: The patient should share with their doctor if they have ever had cytomegalovirus infection (CMV), hepatitis B virus infection (HBV), tuberculosis (TB), herpes zoster (shingles), or kidney and liver disease.

• Pregnancy and Birth Control: The patient should let their doctor know if they are expecting or want to get pregnant. It is important not to get pregnant or father a child during Bendamustine treatment and for three months after. Birth control methods should be used during this time.

• Breastfeeding: If the patient is breastfeeding, they should not continue to do so while receiving Bendamustine treatment.

• Drowsiness: The patient should be aware that Bendamustine injection may cause tiredness. It is advised that people wait to operate machinery or drive until they are familiar with how this drug affects them.

• Tobacco Use: If the patient uses tobacco products like cigarettes, they should inform their doctor. Smoking may reduce the effectiveness of Bendamustine, and the doctor can guide the patient in managing this issue.

What Are the Side Effects of Bendamustine Hydrochloride?

Bendamustine injection may cause side effects. The patient should inform their doctor if any of these symptoms become severe or do not improve:

• Weight loss.

• Sweating.

• Dry skin.

• Vomiting.

• Diarrhea.

• Difficulty falling asleep or staying asleep.

• Sores or white patches in the mouth.

• Anxiety.

• Back, bone, joint, arm, or leg pain.

• Loss of appetite.

• Nausea.

• Constipation.

• Stomach pain or swelling.

• Dry mouth.

• Heartburn.

• Bad taste in the mouth or difficulty tasting food.

• Headache.

• Depression.

• Night sweats.

Some of these side effects can be serious. If any of the following symptoms occur, the patient should contact their doctor immediately or seek emergency medical treatment:

• Shortness of breath.

• Difficulty breathing or swallowing.

• Hives.

• Blistering or peeling skin.

• Fever, cough, chills, or signs of infection.

• Nausea, vomiting, unusual bleeding or bruising, yellowing of the skin or eyes, dark urine, or light-colored stool, tenderness on the right upper side of the stomach.

• Rash.

• Swelling of the eyes, lips, face, arms, tongue, feet, hands, ankles, or lower legs.

• Excessive tiredness or weakness.

• Chest pain.

• Pale skin.

• Itching.

• Fast heartbeat.

• Pain at the injection site.

Bendamustine injection may also lead to infertility in some men, which could be temporary or permanent, and the patient should discuss the associated risks with their doctor. Additionally, some individuals developed different types of cancer while using Bendamustine injection, although it is unclear whether the medication directly caused these cancers. Patients should have a discussion with their doctor regarding the potential risks of receiving this medication.

• Missed Dose: One should call their doctor immediately if they are unable to keep an appointment to receive a dose of Bendamustine injection.

• Overdose: In case of an overdose, it is crucial to contact the poison control helpline or emergency services promptly. Suppose the person affected has collapsed, suffered a seizure, is struggling to breathe, or remains unresponsive. In that case, they may exhibit symptoms of overdose, which can include a rapid, irregular, or pounding heartbeat.

• Storage: When stored in a refrigerator, Bendamustine hydrochloride injection should be maintained between two and eight degrees Celsius (36 and 46 degrees Fahrenheit). Prior to use, let the vial warm up to room temperature (15 to 30 degrees Celsius or 59 to 86 degrees Fahrenheit).

For Doctors:

Indication:

Two different forms of blood malignancies are treated with Bendamustine hydrochloride injection:

• Chronic Lymphocytic Leukemia (CLL): It is for CLL patients, although its efficacy in comparison to other first-line therapies besides Chlorambucil is unknown.

• Non-Hodgkin Lymphoma (NHL): This treatment is for B-cell NHL that is indolent and worsened within six months of receiving Rituximab treatment or medication that contains Rituximab.

Dosing Considerations:

Bendamustine hydrochloride Injection should be administered at a dose of 120 mg/m2 (milligrams per square meter) intravenously on days one and two of a 21-day cycle for a maximum of eight cycles.

If there are severe blood problems (like Grade four hematologic toxicity) or significant non-blood-related issues (at least Grade two), the administration of Bendamustine should be delayed. Once these problems improve to a mild level (Grade one or lower) and the blood counts get better, the doctor can consider starting Bendamustine again. Sometimes, the doctor might also reduce the dose if needed.

For severe blood problems (Grade four), the dose can be reduced to 90 mg/m2 on days one and two of each cycle. If this problem happens again, the dose can be lowered further to 60 mg/m2 on days one and two of each cycle. For non-blood-related problems (Grade three or worse), the same dose reductions can apply if necessary.

The medication Bendamustine hydrochloride injection is packaged in a little bottle. It is a clear or slightly yellow solution with 100 milligrams of the medication in four milliliters of liquid. It is created for several doses and can be used without further dilution.

What Are the Pharmacological Aspects of Bendamustine Hydrochloride?

Mechanism of Action: A unique type of molecule called Bendamustine contains a component that resembles a purine-like benzimidazole ring. This chemical and similar ones can produce unique groups that greatly enjoy adhering to DNA (deoxyribonucleic acid) and other cell components. The DNA may join improperly when they adhere together, which may result in the death of the cells. Cells can be affected by Bendamustine, whether they are dormant or actively dividing.

Pharmacodynamics: When looking at data from adult NHL patients, it was found that as the amount of Bendamustine in the bloodstream (Cmax) increased, so did the likelihood of experiencing nausea. In a study involving 53 patients with indolent NHL and mantle cell lymphoma, the impact of Bendamustine on the QTc interval of the heart was investigated. They received Rituximab followed by Bendamustine. Within one hour after the Bendamustine infusion, there were no significant changes in the QTc interval (a measure of heart rhythm). However, it is important to note that the possibility of delayed effects on the QT interval beyond one hour was not examined.

Pharmacokinetics:

• Absorption: After taking Bendamustine intravenously (IV), the blood usually reaches its greatest concentration (Cmax) at the conclusion of the infusion.

• Distribution: Between 94 percent and 96 percent of Bendamustine adheres to blood proteins. It does not seem to have much interaction with other medications that bind to proteins. Bendamustine has unrestricted movement within red blood cells. According to a study, some Bendamustine-related chemicals remained in the blood longer than Bendamustine itself, indicating that there may be Bendamustine-related substances with longer lives.

• Metabolism: Bendamustine is transformed into various forms in the body by metabolic processes, mostly through the chemical events known as hydrolysis and oxidative reactions. The original Bendamustine appears to be more potent than these new versions. The body's enzymes are responsible for creating a small part of these new forms. Their blood levels are considerably lower than those of the original Bendamustine; therefore, Bendamustine itself still has the most significant impact.

• Elimination: Around 76 percent of Bendamustine is present in the body after administration. A quarter of the dose is excreted in feces, and half is excreted in urine. About 700 mL (milliliter) of Bendamustine are excreted from the body per minute. After a single dose, the traditional form of Bendamustine takes around 40 minutes to leave the body, whereas the new forms take about three hours and 30 minutes.

Overdosage: The highest single dose administered to people was 280 milligrams per square meter. At seven and 21 days after receiving this dose, three out of four individuals experienced some heart-related abnormalities in their ECG (electrocardiogram). One of these individuals experienced a longer QT interval, another experienced a rapid heartbeat, and two more experienced some odd ECG patterns. Additionally, one patient experienced a specific kind of heart block.

However, the patient's cardiac enzymes and blood pumping capacity were both in the normal range. An overdose of Bendamustine hydrochloride cannot be treated with any medication now available. Doctors should provide general assistance if a patient consumes too much of it, such as monitoring their blood pressure and performing ECGs.

Clinical Studies And Efficacy:

Two studies involving 176 indolent B-cell NHL patients (aged 31 to 84, 60 percent men, 89 percent White) treated with Bendamustine hydrochloride revealed common side effects: nausea (75 percent), fatigue (57 percent), vomiting (40 percent), diarrhea (37 percent), and fever (34 percent). Severe side effects (Grade 3 or 4, affecting ≥5 percent): severe fatigue (11 percent), fever with low white blood cell count (6 percent), pneumonia, low potassium levels, and severe dehydration (each 5 percent). Hematologic toxicities were noted, including high blood sugar, elevated creatinine, low sodium, and low calcium. About 37 percent experienced serious adverse reactions, most commonly febrile neutropenia, and pneumonia, with others including kidney, heart, skin, lung issues, and blood disorders. Vigilant monitoring and management of complications are crucial when using Bendamustine for NHL treatment.

What Are the Contraindications to Bendamustine Hydrochloride?

Bendamustine Hydrochloride Injection should not be used in certain situations: If a person is known to have severe allergic reactions (like anaphylaxis) to any of the following substances:

• Bendamustine (the main drug).

• Polyethylene glycol 400.

• Propylene glycol.

• Monothioglycerol.

Warnings and Precautions:

• Myelosuppression: Almost all patients in NHL studies experienced significant myelosuppression (Grade three to four) after receiving Bendamustine hydrochloride, and two percent of these patients died due to myelosuppression-related complications. Blood counts must be regularly monitored, and if recommended levels of recovery have not been reached by the end of the following treatment cycle, dose adjustments may be required.

• Infections: Patients using Bendamustine run the risk of contracting infections like pneumonia and sepsis. Those who have myelosuppression should seek medical attention right away if they show symptoms of infection. It is possible for illnesses like hepatitis B and the cytomegalovirus to reactivate; thus, precautions should be taken before starting treatment.

• Infusion Reactions and Anaphylaxis: Bendamustine may produce infusion reactions, which frequently feature fever, chills, itching, and rash as symptoms. Rarely have there been cases of severe anaphylactic responses. In case of severe responses, patients should be closely watched, and the treatment should be stopped. One option is to take precautions against extreme responses.

• Tumor Lysis Syndrome: The tumor lysis syndrome caused by Bendamustine can manifest as early as the first treatment cycle and, if left untreated, can result in renal damage and even death. Hydration and blood chemistry monitoring are preventive measures. The risk of severe skin poisoning may rise when Bendamustine is used with allopurinol.

• Skin Reactions: Treatment with Bendamustine has been associated with fatal and severe skin reactions, such as Stevens-Johnson syndrome and rash. With more treatment, these side effects can get worse. In the event of severe or persistent skin reactions, Bendamustine may need to be discontinued or terminated.

• Hepatotoxicity: Bendamustine has a history of causing fatal and severe liver damage. Before and during Bendamustine medication, especially in the first three months of treatment, liver chemistry tests should be performed.

• Other Cancers: Patients using Bendamustine have been reported to develop other cancers, such as acute myeloid leukemia and myelodysplastic syndrome.

• Extravasation Injury: Hospitalizations may be required if Bendamustine injuries occur at the infusion site. To avoid such injuries, adequate venous access and thorough monitoring before, during, and after infusion are crucial.

• Toxicity of the Fetus: Research in mice and rats shows that Bendamustine can be harmful to fetuses if given to pregnant mothers. In these investigations, it resulted in reduced body weights and fetal abnormalities. Pregnant women should not use Bendamustine.

What Are the Drug Interactions of Bendamustine Hydrochloride?

The body's interactions between Bendamustine and other medications have not been formally tested. Bendamustine causes the body to produce specific compounds, and certain medications have the ability to either enhance or reduce these substances' levels in the blood.

Some medicines can increase Bendamustine levels while decreasing the amount of chemicals generated. These medicines include Ciprofloxacin and Fluvoxamine. Contrarily, some medications can cause a decrease in Bendamustine levels while increasing the levels of the compounds they create. Smoking and Omeprazole are two examples of such substances.

Use in Specific Populations:

• Pregnancy: When consumed by pregnant women, Bendamustine hydrochloride can be harmful to unborn children. It resulted in birth abnormalities when given to pregnant animals in research on animals. While taking Bendamustine and for three months after stopping treatment, females should not become pregnant. The potential risk to the unborn child should be explained to the woman if she becomes pregnant while taking this medication. While taking Bendamustine, men should also use effective contraception.

• Nursing Mothers: The possibility that Bendamustine enters human breast milk is unknown. Bendamustine has demonstrated possible harm in animal tests; thus, nursing women should determine whether to cease breastfeeding or quit the drug, taking the drug's importance into account. Some pharmaceuticals can transfer into breast milk.

• Children's Use: The usefulness of Bendamustine in children has not been proven. Its safety was compared to that of adults when it was tested on pediatric leukemia patients. In these young individuals, it did not, however, demonstrate any appreciable advantages.

• Renal Impairment: The effects of kidney impairment on the body's ability to break down Bendamustine have not been formally studied. Bendamustine should not be used by anyone with significant renal impairment (defined as CrCL (creatinine clearance) less than 30 milliliter per minute).

• Hepatic Impairment: No formal studies have been done to determine how liver issues affect the body's ability to break down Bendamustine. Bendamustine should not be used by anyone who has moderate or severe liver impairment.

• Gender Effect: In studies for CLL or NHL, there were no appreciable variations in side effects or treatment outcomes between men and women. Both sexes experienced the same effects with Bendamustine.