Bortezomib - Uses, Dosages, Side Effects, and Mechanism of Action

Overview:

Bortezomib is used as an injection in the therapy of cases with multiple myeloma and mantle cell lymphoma. Mantle cell lymphoma is a fast-growing kind of cancer that initiates in the immune system cells. Bortezomib is in a category of medicines known as Antineoplastic agents. It functions by destroying cancer cells.

Describe Bortezomib

Bortezomib is used for injection and is an antineoplastic agent delivered for intravenous (IV) usage only. Bortezomib is a revised form of dipeptidyl boronic acid. The outcome is delivered as a mannitol boronic ester which, in reformed form, includes the mannitol ester in equilibrium with its hydrolysis outcome, the monomeric boronic acid. The medication substance lives in its cyclic anhydride structure as a trimeric Boroxine. The molecular weight of Bortezomib is 384.24. The solubility of Bortezomib, in the form of monomeric boronic acid, in water is 3.3 mg per mL to 3.8 mg per mL in a pH (potential of hydrogen) range of two to six and a half.

Dosage and Administration:

• Dosage in Previously Untreated Multiple Myeloma - Bortezomib is taken as a three to five-second bolus IV injection in a mixture with Melphalan and Prednisone orally for six to nine-week therapy cycles. In cycles one to cycle four, Bortezomib is taken two times per week, that is, on days one, four, eight, eleven, twenty-two, twenty-five, twenty-nine, and thirty-two. In cycles five to nine, Bortezomib is taken one time per week, that is, from days one, eight, 22, and 29. At least 72 hours should elapse between successive doses of Bortezomib.

• Dose Modification Guidelines for Combination Therapy With Bortezomib, Melphalan, and Prednisone - Before beginning any cycle of treatment with Bortezomib together with Melphalan and Prednisone: The platelet count must be greater than or equal to 70 x 109 /L, and the absolute neutrophil counts (ANC) should be greater than or equal to 1.0 x 109 /L. Non-hematological toxicities could have settled to grade 1 or baseline.

Toxicity

• Hematological toxicity at the time of a cycle, if extended Grade 4 neutropenia or thrombocytopenia with or without bleeding is present in the last cycle, then regard deduction of the Melphalan dosage by 25 % in the following cycle.

• If the platelet count is less than or equal to 30 × 109 /L or ANC less than or equal to 0.75 x 109 /L on a Bortezomib dosing day different than day one. In this condition, Bortezomib dosage should be withheld.

• If several Bortezomib doses in successive cycles are withheld because of the toxicity, then the Bortezomib dose might be decreased by one dose level, that is, from 1.3 mg/m2 to one mg/m2 or from 1 mg/m2 to 0.7 mg/m2.

• If the grade is greater than or equal to three non-hematological toxicities, then Bortezomib treatment must be withheld until the toxicity symptoms have settled to grade 1 or baseline. Then, Bortezomib may be restarted with one dose level deduction that is from 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2. For Bortezomib-associated neuropathic ache or peripheral neuropathy, stop or modify Bortezomib.

• Dosage in Relapsed Multiple Myeloma and Mantle Cell Lymphoma - Bortezomib in 1.3 mg/m2 per dose is accepted as a three to five-second bolus intravenous injection two times a week for two weeks, then by a ten day rest period. For elongated treatment of more than eight cycles, Bortezomib may be taken on the standard timetable or on a maintenance schedule of one week for four weeks, obeyed by a 13-day rest time.

• Dose Modification Guidelines for Relapsed Multiple Myeloma and Mantle Cell Lymphoma - The treatment should be withheld at the beginning of any grade 3 non-hematological or grade 4 hematological toxicities except neuropathy. Once the manifestation of the toxicity has settled, Bortezomib treatment may be restarted at a 25 % lesser dose. Cases with preexisting painful neuropathy must be managed with Bortezomib only after a cautious risk-benefit examination.

• Administration Precautions - The medicine quantity included in one vial is 3.5 mg may increase the normal dose needed. Cautiousness must be utilized in estimating the dose to control overdose. Bortezomib is an antineoplastic. Approaches for appropriate handling and disposal must be regarded.

• Reconstitution/Preparation for Intravenous Administration - Appropriate aseptic method should be utilized. Reconstitute with 3.5 mL of 0.9 percent of sodium chloride, resulting in a conclusive concentration of 1 mg/mL of Bortezomib. The reconstituted derivative must be a transparent and colorless solution. Parenteral medication products should be examined visually for particulate matter and discoloration before intake whenever solution and receptacle permit. The reconstituted product should not be utilized if any coloration or particulate matter is marked.

Bortezomib possesses no antimicrobial preservative. Reconstituted Bortezomib must be taken within eight hours of preparation. Bortezomib might be reserved at 25ºC when reconstituted as mandated. The reconstituted substance may be held in the original vial and the syringe before administration. The derivative may be reserved for up to eight hours in a syringe; nevertheless, the total storage period for the reconstituted substances must not be more than eight hours when disclosed to regular indoor lighting.

Dosage Forms and Strengths:

Each single-use vial possesses 3.5 mg of Bortezomib as a sterile lyophilized powder.

Contraindications:

Bortezomib is contraindicated in cases with hypersensitivity to boron or mannitol.

Warnings and Precautions:

Bortezomib should be taken under the management of a physician who is an expert in the usage of antineoplastic treatment. Complete blood counts must be observed continually during therapy with Bortezomib.

Use in Pregnancy

• Pregnancy Category D - Females of childbearing possibility should evade becoming pregnant at the time of being in therapy with Bortezomib.

• Peripheral Neuropathy: Bortezomib therapy induces a peripheral neuropathy that is primarily sensory. Nevertheless, cases of intense sensory and motor peripheral neuropathy have been reported. Cases with preexisting manifestations like numbness, ache, or a burning sensation in the feet or hands or indications of peripheral neuropathy may experience deteriorating peripheral neuropathy at the time of therapy with Bortezomib. So in these cases, patients should be closely monitored for the manifestations.

• Hypotension: The incidence of hypotension was 13 %. These circumstances are watched throughout treatment. Cautiousness should be utilized when managing patients with a previous history of syncope, cases receiving medicines known to be connected with hypotension, and cases who are dehydrated. Treatment of orthostatic hypotension or postural hypotension may possess alteration of antihypertensive medicines, hydration, and intake of mineralocorticoids or sympathomimetics.

• Cardiac Disorders: Acute development or worsening of congestive heart failure and the recent beginning of reduced left ventricular ejection fraction have been notified, involving information in cases with no hazard elements for reduced left ventricular ejection fraction. Cases with risk elements for or existing heart disorders must be closely observed.

• Pulmonary Disorders: There has been information on the acute diffuse infiltrative pulmonary disorder of unrecognized etiology, like pneumonitis, interstitial pneumonia, lung infiltration, and acute respiratory distress syndrome in cases taking Bortezomib.

• Reversible Posterior Leukoencephalopathy Syndrome: There has been information on reversible posterior leukoencephalopathy syndrome in patients taking Bortezomib. A brain imaging test, particularly MRI (magnetic resonance imaging), is utilized to verify the diagnosis. In case of developing reversible posterior leukoencephalopathy syndrome, discontinue Bortezomib.

• Gastrointestinal Adverse Events: Bortezomib therapy can induce nausea, diarrhea or constipation, and vomiting. Fluid and electrolyte replacement should be given to control dehydration.

• Thrombocytopenia or Neutropenia: Bortezomib is connected with thrombocytopenia and neutropenia that has a cyclical pattern with nadirs emerging following the final dosage of each cycle and generally regaining before initiation of the succeeding cycle.

1. Tumor Lysis Syndrome: As Bortezomib is a cytotoxic agent and can easily destroy malignant cells, complications of tumor lysis syndrome may happen. Cases at risk of tumor lysis syndrome are those with increased tumor burden before therapy.

2. Hepatic Events: Acute liver failure has been notified in cases taking multiple concomitant medicines and with severe underlying medical illnesses. Additional documented hepatic circumstances possess boosts in liver enzymes, hyperbilirubinemia, and hepatitis condition.

For Patients:

What Is Multiple Myeloma?

Multiple myeloma is a cancer that begins in a kind of white blood cell known as a plasma cell. Healthy plasma cells support fighting infections by producing antibodies that identify and attack germs. Cancerous plasma cells collect in the bone marrow and group healthy blood cells in this case. Rather than creating useful antibodies, the cancer cells create abnormal proteins that can generate complications.

How Should Bortezomib Be Used?

Bortezomib is available as a solution to inject into a vein or subcutaneously under the skin. Bortezomib is provided by a doctor or nurse. The dosing schedule will rely on the condition, the additional medications that are used, and how well the body reacts to therapy.

What Are the Precautions to Be Followed While Taking Bortezomib?

Before Taking Bortezomib:

• Inform the doctor and healthcare provider in case of allergy to Bortezomib, Mannitol, other medications, Boron, or any of the components in Bortezomib. Request the healthcare provider for an ingredient list.

• Inform the doctor and pharmacist what additional prescription and nonprescription medicines, vitamins, or nutritional supplements they are taking or intend to take. Be certain to say any of the following: Clarithromycin, certain antifungals, medicines to manage diabetes and high blood pressure, specific medicines to manage human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS), particular medicines to manage seizures. The doctor may require altering medication doses or observing carefully for adverse effects. Many additional medicines may also interact with Bortezomib, so be certain to inform the doctor about all the medicines that are taken, even those that do not seem on this list.

• Inform the doctor if any herbal products are taken, particularly St. John's wort.

• Inform the doctor if there is any familial history of heart disease, herpes infection, diabetes, high cholesterol, altered blood pressure, peripheral neuropathy, kidney disease, or liver disease. Also, inform the doctor if there is any habit of smoking or drinking large amounts of alcohol.

• Inform the doctor in case of pregnancy or intend to become pregnant. Bortezomib may hurt the fetus. Usage of birth control to avert pregnancy during treatment with Bortezomib and for at least seven months following the final dosage is required.

• Do not breastfeed at the time of therapy with Bortezomib and for two months following the final dose.

• In case of undergoing any kind of surgery involving dental surgery, inform the doctor or dentist about Bortezomib.

• The patient should have knowledge that Bortezomib may cause drowsiness and lightheaded or induce fainting or altered vision.

What Should Special Dietary Instructions Be Followed While Taking Bortezomib?

• Inform the doctor about consuming grapefruit and ingesting grapefruit juice while utilizing this medicine.

• Drink an abundance of fluids daily at the time of therapy with Bortezomib, particularly if the patient vomits or has diarrhea.

What Should Be Done in Case of a Forgotten Dose?

In case of a missed appointment to acquire a dose of Bortezomib, contact the doctor immediately.

What Are the Side Effects of Bortezomib?

Bortezomib may induce side effects. Inform the doctor if any of these manifestations, or those in the certain precautions section, are intense or do not go away:

• Weakness.

• Fatigue.

• Nausea and vomiting.

• Diarrhea, constipation, and loss of appetite.

• Aches in head and stomach.

• Aches, redness, and bleeding at the injection site.

• Trouble falling asleep.

Some side effects can be severe. If one undergoes any of these manifestations, contact the doctor instantly:

• Weakness in the extremities, alterations in the sense of touch, aches, burning, and numbness in the hands, arms, and legs.

• Sudden shooting ache, continuous burning ache, or muscle weakness.

• The difficulty of breathing, rapid heartbeat, dizziness, pale skin, and tiredness.

• Swelling of the feet, ankles, or lower legs.

• Hives, skin rash, itching.

• Hoarseness, hardship in swallowing or breathing, or swelling.

• Fever, chills, cough, or additional manifestations of infection.

• Bleeding.

• Black-colored stools, red blood in the stools, bloody vomit, coffee ground-like material in the vomitus.

• Altered speech or incapability to speak or comprehend speech, confusion, failure of the capability to move a body part, altered vision, coordination loss.

• Fainting, dizziness, and nausea.

• Chest pressure or ache, rapid heartbeat, inflammation of the ankles or feet, or shortness of breath.

• Cough and difficulty breathing.

• Headache, seizures, fatigue, or vision alteration.

• Purple dots under the skin.

How Is Bortezomib Stored and Disposed of?

Bortezomib will be stored in the medical hospital or clinic.

How Is Bortezomib Overdose Managed?

In the matter of overdose, contact the poison control helpline. If the patient has collapsed, had a seizure, has difficulty breathing, or cannot be aroused, instantly call emergency services. Manifestation of overdose may involve the following:

• Fainting and dizziness.

• Altered vision.

• Unusual bleeding.

For Doctors:

Adverse Reactions:

• Peripheral Neuropathy - The incidence of peripheral neuropathy was increased among cases with mantle cell lymphoma and corresponded to multiple myeloma

• Hypotension Cases - The incidence of hypotension was comparable in cases with multiple myeloma and those with mantle cell lymphoma.

• Cardiac Disorders - Angina pectoris, atrial flutter, bradycardia, sinus arrest, amyloidosis, total atrioventricular block, ischemia, myocardial infarction, and pericardial effusion.

• Thrombocytopenia or Neutropenia - Bortezomib-associated thrombocytopenia was distinguished by a reduction in platelet count at the time of the dosing period and a retrieval toward baseline at the time of the ten-day rest period at each therapy cycle. Neutrophil counts declined during the Bortezomib dosing period and returned toward baseline during the tenth-day rest period during each therapy cycle.

Drug Interactions:

• Ketoconazole - Co-administration of Ketoconazole, which is a potent CYP3A inhibitor, improved the exposure of Bortezomib.

• Melphalan-Prednisone - Co-administration of Melphalan-Prednisone raised the exposure of Bortezomib. Nevertheless, this boost is improbable to be clinically relevant.

• Omeprazole - Co-administration of Omeprazole, a potent inhibitor of CYP2C19, had no impact on the exposure of Bortezomib.

• Cytochrome P450 - Patients who concomitantly receive Bortezomib and medications that are inhibitors of cytochrome P450 3A4 or inducers of cytochrome P450 3A4 should be closely observed for either toxicities or decreased efficacy.

Use in Specific Populations:

• Pregnancy - There are no satisfactory and well-controlled investigations on pregnant women. If Bortezomib is utilized during pregnancy, or if the patient becomes pregnant while acquiring this medication, the patient should be informed of the potential hazard to the fetus.

• Nursing Mothers - It is unknown whether Bortezomib is secreted in human milk. As many medications are secreted in human milk, and because of the possibility of severe adverse reactions in nursing infants from Bortezomib, a determination should be created whether to stop nursing or to stop the medication, taking into consideration the significance of the medication to the mother.

• Geriatric Use - Not many differences are noticed, but the increased sensitivity of certain older people cannot be ruled out.

• Patients With Renal Impairment - The pharmacokinetics of Bortezomib are not affected by the degree of renal impairment. Thus, dosing alteration of Bortezomib is not required for cases with renal insufficiency. Since dialysis may decrease Bortezomib concentrations, the medicine should be taken after the dialysis process.

• Patients With Diabetes - Patients on oral antidiabetic drugs obtaining Bortezomib therapy may demand close monitoring of their blood glucose levels and alteration of the dose of their antidiabetic drug.

Clinical Pharmacology

Mechanism of Action:

Bortezomib has a chymotrypsin-like activity of the 26S proteasome reversible inhibitor in mammalian cells. The 26S proteasome is a big protein complex that impairs ubiquitinated proteins. The ubiquitin-proteasome pathway is essential in controlling the intracellular concentration of particular proteins, thereby keeping homeostasis within cells. Inhibition of the 26S proteasome controls this targeted proteolysis, which can impact multiple signaling cascades in the cell. This disturbance of normal homeostatic mechanisms can guide cell death. Investigations have explained that Bortezomib is cytotoxic to various cancer cell kinds in vitro. Bortezomib induces a delay in tumor development in vivo in nonclinical tumor standards involving multiple myeloma.

Pharmacodynamics

After two weeks of administration of one mg/m2 and 1.3 mg/m2, Bortezomib doses in complete blood were checked five minutes following medicine administration. Relative maximum inhibition of 20S proteasome activity was checked between one and 1.3 mg/m2 doses. Maximal inhibition varied from 70 to 84 % and from 73 to 83 % for the one mg/m2 and 1.3 mg/m2 dose regimens, respectively.

Nonclinical Toxicology

• Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenicity investigations have not been performed with Bortezomib. Bortezomib exhibited clastogenic action in the in vitro chromosomal aberration assay utilizing Chinese hamster ovary cells. It was not genotoxic when experimented with in mice in the in vitro mutagenicity assay and in vivo micronucleus assay.

• Animal Toxicology - Investigations in monkeys demonstrated that administration of dosages around twice the suggested clinical dose induces heart rate elevations, heeded by profound progressive hypotension, bradycardia, and even death 12 to 14 hours post-dose.