Bortenat-3-5-mg-Injection

Brand name: Bortenat Active substance: Bortezomib Strength: 3.5Mg Mfg: Natco pharma Pack: one vial in a carton Classified as: Anti-neoplastic agent Route of administration: Bolus... read more

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Drug profile of Bortenat 3.5mg

Bortenat 3.5mg is a derivative of pyrazine & boronic acid that behaves as an unpredictable proteasome inhibitor.

Bortenat 3.5mg is available as lyophilized powder which is given as bolus intravenous injection, which is chemically classified as analogue of dipeptide boronic acid containing an anti-neoplastic activity.

Bortenat 3.5mg is a FDA approved product containing active substance known as Bortezomib.

Bortenat 3.5mg is considered as a targeted therapy, majorly used in multiple myeloma & mantle cell lymphoma.

Bortenat 3.5mg are considered as;

Proteasome inhibitor

Anti-neoplastic

Targeted therapy

Bortenat 3.5mg is a cytotoxic drug, use cautiously


Prescribing information of Bortenat 3.5mg

The major prescribing information of Bortenat is;

Multiple myeloma therapy: Bortenat 3.5mg drug is used in this condition

Mantle cell lymphoma therapy: Patients, who are not responding to at least one chemotherapy regimen, should be followed by treated with Bortenat therapy.

 

Mechanism of Bortenat 3.5mg

Bortenat 3.5mg is an unstable inhibitor of chymotrypsin like activity of 26S proteasome present in human cells.

The degradation of ubiquitinated proteins are induced by 26S proteasome which is a high protein complex.

The intercellular concentration of specific proteins is regulated by proteasome pathway which manages the homeostasis present within the cells.

 The prohibition of 26S proteasome impedes this targeted proteolysis; this may affect the multiple signaling cascades within the cells.

 The interruption of normal homeostatic mechanism leads to cell lysis.

 

Absorption

Following intravenous administration of 1mg/m2 & 1.3mg/m2 doses, causes maximum plasma concentration time after the initial dose were 57 & 112ng/ml. the absorption of Bortenat is occurs in good manner.

 

Distribution

Volume of distribution of Bortenat 3.5mg is occurs relatively 498 to 1884L/m2.

Bortezomib is highly bound to human plasma protein by 83%.

 

Metabolism

The metabolism of Bortenat 3.5mg is majorly induced by human liver microsomes in vivo.

The Bortezomib is metabolized by undergoes oxidation with the help of CYP 450 isoenzymes like 3A4, 2C19, & 1A2.

Deboronation is the major metabolic pathway of Bortenat, which leads to form 2 deboronated metabolites that undergo hydroxylation to various metabolites, which may inactive as 26S proteasome inhibitors.

 

Excretion

The terminal half life of Bortezomib is 40 hours to 193 hours.

The total creatinine clearance range of Bortezomib is 102L/hr & 112L/hr, followed by the dose of 1 & 1.3mg/m2.

The route of excretion has not been evaluated.

 

When to take the Bortenat 3.5mg

Bortenat 3.5mg should be administered as bolus intravenous injection, do not use any other route.

The IV administration of Bortenat 3.5mg should be within a period of 3 to 5 seconds through bolus IV.

It should be administered with or without food.

 

Dosage regimens of Bortenat 3.5mg

Multiple myeloma:

The usual prescribed dose of Bortenat is 1.3mg/m2. The concentration of Bortezomib is 1mg/ml while administrating through IV.

Bortezomib should be used in combination with oral melphalan & oral prednisolone for the period of nine 6 week therapy cycles.

In cycle 1 to 4, the frequency of Bortezomib should be given as a twice weekly.

In cycles 5 to 9, the frequency reduced to once weekly.

Between successive doses of Bortezomib, at least 72 hours should be elapsed.

Before starting the treatment with Bortenat, patients must be examining with;

Platelet counts 70 x 109 L, neutrophils counts 1 x 109L

Non hematological toxicity resolved to grade 1.

Dose alteration in combination therapy;

In grade IV toxicity, hematological toxicity, the dose of melphalan should be reduced by 25%.

If counts of platelets are not above 30 x 109L, interrupt the dose of Bortenat

Due to toxicity, the consecutive doses of Bortezomib should be interrupting and follows the dose of Bortenat reduced from 1.3mg/m2 to 1mg/m2; from 1mg/m2 to 0.7mg/m2.

In grade III or any severe hematological toxicity: Interrupt the Bortenat therapy until the toxicity resolved to grade I or 0.

For mantle cell lymphoma & multiple myeloma in relapse state:

 Bortenat should be administered IV as dose of 1.3mg/m2 for 2 weeks as twice weekly day 1.4.8 & 11 followed by 10 day rest period days 12 to 21.

For prolonged therapy, more than 8 cycles Bortezomib should be given as IV as standard dose for 4 weeks as once a week followed by 13 days rest period days 23 to 35.

Dose alteration in peripheral neuropathy:

Grade I toxicity: no dosage adjustment should be required

Grade I with pain or grade II: The dose of Bortenat should be reduced to 1mg/m2

Grade II with pain or grade III: Interrupt the treatment till the toxicity changes to grade I or 0.

Grade IV: Stop the treatment.

Dose alteration in liver impairment:

In mild condition: No alteration occurs

In moderate to severe: The dose reduced to 0.7mg/m2 on first cycle, then dose increased to 1mg/m2 or further reduction is required to 0.5mg/m2 based on patients tolerability.

Reconstitution of Bortenat 3.5mg:

Bortenat 3.5mg vial containing 3.5mg lyophilized powder of Bortezomib as an active substance.

The Bortenat 3.5mgcontent should be reconstituted by using 3.5ml of 0.9% of sodium chloride solution.

It is single use vial, the remaining portion of Bortenat solution should be discarded after use.

In this 3.5ml solution containing 3.5mg of drug; 1mg/ml

 

Bortenat 3.5mgcaused side effects

The following adverse effect are most probably occurs during the Bortenat 3.5mg therapy;

Hypotension

Cardiac toxicity

Pulmonary toxicity

Peripheral neuropathy

Posterior reversible encephalopathy syndrome

GI toxicity

Thrombocytopenia or neutropenia

Tumor lysis syndrome

Liver toxicity

Some common side effects;

Nausea

Diarrhea

Fatigue

Peripheral neuropathy

Thrombocytopenia

Vomiting

Anorexia

Pyrexia

Paresthesia

Anemia

Headache

Neutropenia

Rash

Loss of appetite

Dyspnea

Abdominal pain

Weakness

Herpes zoster

Insomnia

Neuralgia

Post marketing reports;

Cardiac tamponade

Deafness bilateral

Optic neuropathy

Blindness

Ischemic colitis

Multifocal leukoencephalopathy syndrome

Acute diffuse infiltrative pulmonary disease

Anaphylactic reactions

 

Drug- drug interaction

Co administration of Bortenat 3.5mg with strong CYP3A4 inhibitors causes adverse effects related to Bortezomib, because of increasing the exposure of Bortezomib. To overcome the problem, the dose of Bortenat 3.5mg should be reduced.

Avoid combination of Bortenat 3.5mg with strong CYP3A4 inducers; this combination may produce depletion of exposure of Bortezomib. This concludes as loss of therapeutic effect. Example for strong CYP3A4 inducers is st. Johns wort.

Concurrent use of dexamethasone does not produce any effect on exposure of Bortezomib.

Concurrent use of melphalan prednisolone with Bortenat 3.5mg has no effect on exposure of Bortezomib.

 

Food drug interaction

Vitamin C, an ascorbic acid leads to reduce the effectiveness of Bortezomib.

During multiple myeloma treatment, some food should not be taken,

Raw sprouts

Uncooked eggs

Unpasteurized dairy

Uncooked meats, seafood

Vitamin & mineral supplements should be used cautiously during Bortenat therapy.

 

Possible contraindications

Bortenat 3.5mg should not be administered through intrathecal route, some fatal events may occur.

Anaphylactic reactions may occur while patients may contraindicate to the component present in Bortenat 3.5mg injection.

 

Safety measures

Peripheral neuropathy: Patients may suffered with some grade II or III toxicity during the therapy of Bortenat, in this conditions patient should be examine with the symptoms associated to toxicity.

For avoiding this adverse, dose reduction is required and maintains the toxicity grade level to I or 0.

Provide supportive treatment or discontinue the therapy with Bortenat.

Hypotension: The hypotension occurrence should be happens during the treatment of MM or MCL with Bortenat.

If patient with history of syncope, Bortenat 3.5mg should be used carefully in this patient. The management of postural hypotension may include as anti-hypertensive drugs, hydration, providing with mineralocorticoids or sympathomimetics.

 Cardiac toxicity: Acute aggravation of congestive heart failure or new commencement of decreased left ventricular ejection may occur during the therapy.

This may leads to QT prolongation

To overcome the problems, patients must be

Monitor with ECG

Provide with general supportive therapy

Discontinue with treatment

Pulmonary toxicity: In a trial period, patient receiving high dose of cytarabine with daunorubicin & Bortezomib should be suggested for acute myelogenous leukemia died for the reason of acute respiratory distress syndrome.

To avoid the problems, therapy should be postponed until the adverse will recovered.

Posterior reversible encephalopathy syndrome: Analysis the patient whether suspected with pulmonary toxicity or not.

Provide with supportive measures

Discontinue the treatment, if disease progression persists.

Gastrointestinal toxicity: Fluid & electrolyte replacement should be given to the patients.

Hematological toxicity: Check the blood cell counts during or before the treatment starts.

Tumor lysis syndrome: patient with high tumor burden before the treatment may suspected highly with tumor lysis syndrome. Monitor the patients by giving appropriate precautions.

Liver toxic: Monitor AST, ALT, bilirubin & other liver enzymes frequently in both before & during the therapy time.

Embryo fetal toxicity: Bortenat is contraindicated to pregnancy and lactation period.

 

Pregnancy and lactation

Pregnancy category D

Bortenat 3.5mg should not be used in pregnancy condition, causes embryo fetal damage

Bortenat 3.5mg should not be allowed for lactating women, metabolites are present in human milk.

The potency of Bortezomib has not been evaluated in pediatric patients.

Renal damage patients: Dialysis should diminish the concentration of Bortezomib; no dosage adjustment is required for renal insufficiency patients.

Bortezomib treatment should not be preferred on dialysis period; it must be used after dialysis procedure.

The initial dose of Bortezomib is reduced in case of moderate & severe hepatic impaired patients.

In diabetic patients, who are receiving oral anti-diabetic medications should be use Bortezomib carefully by monitoring blood glucose levels frequently.

Dose adjustment of anti-diabetic medication should be necessary.

 

Storage and handling

The unopened vial should be stored at 20oC to 25oC excursion between 15oC to 30oC.

Protect from moisture, heat & light.

 

Missed dose

The missed dose should be avoided. If patient missed the cycles, must consult with medical oncologist.

 

Over dosage

The over dose of Bortenat 3.5mg causes acute commencement of symptomatic hypotension and thrombocytopenia.

For over dose condition, the manifestation should be monitored frequently.

Provide preventive and supportive measures for over dosage of Bortenat.

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