BORTENAT 2MG, 4 VIAL

BORTENAT2MG

INGREDIENT-

Bortenat injection contain Bortezomib

INTRODUCTION-

Bortenat 2mg Injection is used in the treatment of multiple myeloma and mantle-cell lymphoma.

Bortezomib (originally PS-341 and marketed as Velcade by Millennium Pharmaceuticals) is the first therapeutic proteasome inhibitor to be tested in humans. 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. However, in cancerous cells, proteasome activity degrades pro-apoptotic proteins such as p53 that would normally result in programmed cell death of the dysfunctional cells. Proteasome inhibitors such as bortezomib interrupt this process, resulting in destruction of cancerous cells.

Bortezomib is approved in the U.S. 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.

Structure of Bortezomib

PHARMACOLOGY-

---PHARMACODYNAMICS-

Bortenat is a drug that inhibits the mammalian 26S proteasome. 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 prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that Bortenat is cytotoxic to a variety of cancer cell types in vitro. Bortenat causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma. Tumor cells, that is, rapidly dividing cells, appear to be more sensitive to proteasome inhibition.

MECHANISM OF ACTION-

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). Pharmacodynamics are measured by measuring proteasome inhibition in peripheral blood mononuclear cells. The much greater sensitivity of myeloma cell lines and mantle cell lines to proteasome inhibition compared with normal peripheral blood mononuclear cells and most other cancer cell lines are poorly understood

---- Pharmacokinetics

-ABSORPTION AND DISTRIBUTION-

After subcutaneous administration, peak plasma levels are ~25-50 nM and this peak is sustained for 1-2 hrs. After intravenous injection, peak plasma levels are ~500 nM but only for ~5 minutes, after which the levels rapidly drop as the drug distributes to tissues (volume of distribution is ~500 L). Both routes provide equal drug exposures and generally comparable therapeutic efficacy. –

METABOLISM-

In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes 3A4, 2C19, and 1A2, while bortezomib metabolism by CYP 2D6 and 2C9 enzymes is minor. The major metabolic pathway is deboronation to form 2 deboronated metabolites that subsequently undergo hydroxylation to several metabolites which are inactive as 26S proteasome inhibitors.

TOXICITY-

Cardiovascular safety pharmacology studies in monkeys show that lethal IV doses are associated with decreases in blood pressure, increases in heart rate, increases in contractility, and ultimately terminal hypotension. In monkeys, doses of 3.0 mg/m2 and greater (approximately twice the recommended clinical dose) resulted in progressive hypotension starting at 1 hour and progressing to death by 12 to 14 hours following drug administration.

-Protein binding –

83% over the concentration range of 100-1000 ng/ml.

-Bortezomib - Drug Interactions

If you use other drugs or over the counter products at the same time, the effects of Bortezomib may change. This may increase your risk for side-effects or cause your drug not to work properly. Tell your doctor about all the drugs, vitamins, and herbal supplements you are using, so that you doctor can help you prevent or manage drug interactions.

Bortezomib may interact with the following drugs and products:

-Clopidogrel

-Etravirine

-Ketoconazole

-Rifampin

-Ritonavir

-St. John's Wort

Precautions-

Before using Bortezomib, inform your doctor about your current list of medications, over the counter products (e.g. vitamins, herbal supplements, etc.), allergies, pre-existing diseases, and current health conditions (e.g. pregnancy, upcoming surgery, etc.). Some health conditions may make you more susceptible to the side-effects of the drug. Take as directed by your doctor or follow the direction printed on the product insert. Dosage is based on your

condition. Tell your doctor if your condition persists or worsens. Important counseling points are listed below.

-Avoid driving or operating heavy machinery if you experience dizziness and fatigue

-Breastfeeding

-Congestive Heart Failure

-Consult your doctor if you have signs of serious brain infections

-Consult your doctor in case of liver disease, kidney or heart disease, fever with rash or genital sores, diabetes, low number of red blood cells and white blood cells, bleeding problems

-Contact physician if you experience new or worsening peripheral neuropathy symptoms (tingling, burning, numbness, pain in hands or feet)

Bortezomib–Contraindications-

Hypersensitivity to Bortezomib is a contraindication. In addition, Bortezomib should not be used if you have the following conditions:

-Allergic

-Chest pain

-Diarrhea

-Hypersensitivity to bortezomib, boron, or mannitol

-Intrathecal administration

-Simultaneous administration of green tea extract

Over dosage of Bortezomib

Do not use more than prescribed dose. Taking more medication will not improve your symptoms; rather they may cause poisoning or serious side-effects. If you suspect that you or anyone else who may have overdosed of Bortezomib, please go to the emergency department of the closest hospital or nursing home. Bring a medicine box, container, or label with you to help doctors with necessary information.

Do not give your medicines to other people even if you know that they have the same condition or it seems that they may have similar conditions. This may lead to overdosage.

Storage of Bortezomib

Store medicines at room temperature, away from heat and direct light. Do not freeze medicines unless required by package insert. Keep medicines away from children and pets.

Do not flush medications down the toilet or pour them into drainage unless instructed to do so. Medication discarded in this manner may contaminate the environment. Please consult your pharmacist or doctor for more details on how to safely discard Bortezomib.