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Bortezomib; Uses, Dosage, Side Effects, Interactions, Pregnan

Bortezomib is a dipeptide boronic acid analog with antineoplastic activity. Bortezomib reversibly inhibits the 26S proteasome, a large protease complex that degrades ubiquitinated proteins. By blocking the targeted proteolysis normally performed by the proteasome, bortezomib disrupts various cell signaling pathways, leading to cell cycle arrest, apoptosis, and inhibition of angiogenesis. Specifically, the agent inhibits nuclear factor (NF)-kappaB, a protein that is constitutively activated in some cancers, thereby interfering with NF-kappaB-mediated cell survival, tumor growth, and angiogenesis. In vivo, bortezomib delays tumor growth and enhances the cytotoxic effects of radiation and chemotherapy.

Bortezomib is an anti-cancer drug and the first therapeutic proteasome inhibitor to be used in humans. Proteasomes are cellular complexes that break down proteins. The boron atom within bortezomib catalytically binds the active site of the 26S proteasome with high affinity and specificity, thereby resulting in cell cycle arrest and apoptosis. In normal cells, the proteasome is involved in degradation of ubiquitylated proteins that have been tagged for destruction because they are damaged or unneeded by the cell. In some cancers, the proteins that normally kill cancer cells are broken down too quickly. Bortezomib interrupts this process and lets those proteins kill the cancer cells. It is approved in the U.S. and Europe for treating relapsed multiple myeloma and mantle cell lymphoma. In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease.

Mechanism of Action of Bortezomib

Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The active site of the proteasome has chymotrypsin-like, trypsin-like, and postglutamyl peptide hydrolysis activity. The 26S proteasome degrades various proteins critical to cancer cell survival, such as cyclins, tumor suppressors, BCL-2, and cyclin-dependent kinase inhibitors. Inhibition of these degradations sensitizes cells to apoptosis. Bortezomib is a potent inhibitor of 26S proteasome, which sensitizes activity in dividing multiple myeloma and leukemic cells, thus inducing apoptosis. In addition, bortezomib appears to increase the sensitivity of cancer cells to traditional anticancer agents (e.g., gemcitabine, cisplatin, paclitaxel, irinotecan, and radiation).

Bortezomib, a modified dipeptidyl boronic acid, is an antineoplastic agent. The drug reversibly inhibits the 26S proteasome, a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome by bortezomib prevents targeted proteolysis and causes disruption of normal homeostatic mechanisms, which can lead to cell death. In vitro studies indicate that bortezomib is cytotoxic to a variety of cancer cell types. Bortezomib has been shown to cause a delay in tumor growth in vivo in tumor models, including multiple myeloma.

Indications of Bortezomib

Lymphoma
Mantle Cell Lymphoma
Multiple Myeloma
Mantle Cell Lymphoma (MCL)
Treatment of mantle cell lymphoma
Treatment of multiple myeloma (who had previously responded to treatment with this drug and who have relapsed at least 6 months after completing treatment)

From FDA Level

Bortezomib Accord as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone is indicated for the treatment of adult patients with progressive multiple myeloma who have received at least 1 prior therapy and who have already undergone or are unsuitable for hematopoietic stem cell transplantation.
Bortezomib Accord in combination with melphalan and prednisone is indicated for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for high dose chemotherapy with hematopoietic stem cell transplantation.
Bortezomib Accord in combination with dexamethasone, or with dexamethasone and thalidomide, is indicated for the induction treatment of adult patients with previously untreated multiple myeloma who are eligible for high-dose chemotherapy with hematopoietic stem cell transplantation.
Bortezomib Accord in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma who are unsuitable for hematopoietic stem cell transplantation.
Bortezomib Hospira as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone is indicated for the treatment of adult patients with progressive multiple myeloma who have received at least 1 prior therapy and who have already undergone or are unsuitable for hematopoietic stem cell transplantation.
Bortezomib Hospira in combination with melphalan and prednisone is indicated for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with hematopoietic stem cell transplantation.
Bortezomib Hospira in combination with dexamethasone, or with dexamethasone and thalidomide, is indicated for the induction treatment of adult patients with previously untreated multiple myeloma who are eligible for high-dose chemotherapy with hematopoietic stem cell transplantation.
Bortezomib Hospira in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma who are unsuitable for hematopoietic stem cell transplantation.
Bortezomib SUN as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone is indicated for the treatment of adult patients with progressive multiple myeloma who have received at least 1 prior therapy and who have already undergone or are unsuitable for hematopoietic stem cell transplantation.
Bortezomib SUN in combination with melphalan and prednisone is indicated for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with hematopoietic stem cell transplantation.
Bortezomib SUN in combination with dexamethasone, or with dexamethasone and thalidomide, is indicated for the induction treatment of adult patients with previously untreated multiple myeloma who are eligible for high-dose chemotherapy with hematopoietic stem cell transplantation.
Bortezomib SUN in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma who are unsuitable for hematopoietic stem cell transplantation.

Contra-Indications of Bortezomib

Diabetes
Extreme Loss of body water
Decreased blood platelets
Decreased neutrophils a type of white blood cell
Peripheral neuropathy
The increased pressure of the pulmonary circulation
Chronic heart failure
Blood pressure drop upon standing
Abnormally low blood pressure
Pneumonia
Interstitial pneumonitis
Acute respiratory distress syndrome
Blocked bowels with decreased peristaltic movement
Liver problems
Pregnancy
A Mother who is producing milk and breastfeeding
Brain-capillary leak syndrome

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Dosages of Bortezomib

Strengths: 3.5 mg

Lymphoma

Dosage in previously united mantle cell lymphoma

1.3 mg/m2 as a bolus IV injection twice weekly in combination with IV rituximab, cyclophosphamide, doxorubicin, and oral prednisone for two weeks (days 1, 4, 8, and 11) followed by a ten day rest period (days 12 through 21)

For use in the treatment of release mantle cell lymphoma

Usual dose: 1.3 mg/m2 as a bolus IV injection or subcutaneously twice weekly for two weeks (days 1, 4, 8, and 11) followed by a ten day rest period (days 12 through 21). Therapy extending beyond 8 cycles may be administered by the standard schedule or may be given once weekly for 4 weeks (days 1, 8, 15, and 22), followed by a 13-day rest (days 23 through 35).

Multiple Myeloma

For use in the treatment previous treatment of multiple myeloma

Usual dose: 1.3 mg/m2 administered as a 3 to 5 second bolus IV injection or subcutaneously in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles:
In cycles 1 through 4, bortezomib is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29, and 32). In cycles 5 through 9, bortezomib is administered once weekly (days 1, 8, 22, and 29).

For use in the treatment of release multiple myeloma

Usual dose: 1.3 mg/m2 as a bolus intravenous injection or subcutaneously twice weekly for two weeks (days 1, 4, 8, and 11) followed by a ten day rest period (days 12 through 21). Therapy extending beyond 8 cycles may be administered by the standard schedule or may be given once weekly for 4 weeks (days 1, 8, 15, and 22), followed by a 13-day rest (days 23 through 35).

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Side Effects of Bortezomib

The most common

More common

Fast or irregular heartbeat
appetite loss
changes in nails
constipation
fatigue
fever
Back pain
dizziness
headache
increased cough
Acid or sour stomach
decreased appetite
Agitation
chest congestion
chest pain
cold sweats
confusion
decreased sexual ability or desire
stomach or abdominal cramps, gas, or pain
trouble sleeping

Less common

bleeding gums
blood in the urine or stools
chest pain
diarrhea
Burning, crawling, itching, numbness, prickling, “pins and needles“, or tingling feelings
difficulty in moving
muscle stiffness
redness of the face, neck, arms and occasionally, upper chest
lack or loss of strength
muscle spasm
difficult or labored breathing
dry mouth
headache
irritability
lack or loss of strength
loose stools
loss of interest or pleasure
muscle stiffness
night sweats
passing gas
stomach discomfort, upset, or pain
swollen joints
trouble concentrating
increased blood pressure

Drug Interactions of Bortezomib

Bortezomib may interact with following drugs, supplements & may change the efficacy of the drug

alpha blockers (e.g., alfuzosin, doxazosin, silodosin, tamsulosin)
anticancer medications (e.g., cabazitaxel, docetaxel, doxorubicin, etoposide, ifosfamide, irinotecan, vincristine)
“azole” antifungal medications (e.g., fluconazole, itraconazole, ketoconazole)
beta-blockers (e.g., atenolol, propranolol, metoprolol)
barbiturates (e.g., butalbital, pentobarbital, phenobarbital)
benzodiazepines (e.g., chlordiazepoxide, clonazepam, diazepam, lorazepam)
calcium channel blockers (e.g., nifedipine, diltiazem, verapamil, amlodipine, felodipine)
bupropion
estrogen and estrogen-containing birth control (women)
medications that promote loss of bone density (e.g., prednisone)
testosterone and androgens (men)
corticosteroids (e.g., dexamethasone, prednisone, methylprednisolone)
cyclosporine
“gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
losartan
macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)
metronidazole
montelukast
norfloxacin
ondansetron
carbamazepine
phenytoin
proton pump inhibitors (PPIs; e.g., esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole)
selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine,paroxetine, sertraline)
sildenafil
“statin” anticholesterol medications (e.g., atorvastatin, lovastatin, simvastatin)
tadalafil
tamoxifen
tetracycline
theophylline
tocilizumab
tolterodine
tramadol
other selective serotonin reuptake inhibitors (SSRIs;e.g., citalopram, fluoxetine, sertraline)
5-HT3 antagonists (e.g., granisetron, ondansetron)
tamsulosin
tapentadol
thiazide diuretics (e.g., hydrochlorothiazide, indapamide)
tramadol
tricyclic antidepressants (e.g., nortriptyline, amitriptyline, imipramine,
trimethoprim
other tyrosine kinase inhibitors (e.g., dasatinib, imatinib, nilotinib, sunitinib)
tetracycline
tocilizumab
vitamin C

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Pregnancy & Lactation of Bortezomib

FDA Pregnancy Category D

Pregnancy

No studies have been conducted to determine the effect of bortezomib on an unborn baby if the medication is used during pregnancy. Women should avoid becoming pregnant while taking bortezomib. Men and women should use effective contraception during bortezomib treatment and for the 3 months following treatment. If you become pregnant while using this medication, contact your doctor immediately.

Lactation

It is not known if bortezomib passes into breast milk. If you are a breastfeeding mother and are taking this medication, it may affect your baby. Women should not breast-feed while taking bortezomib.The safety and effectiveness of bortezomib have not been established for use by children and adolescents less than 18 years of age