Generic Times: Product Profiles

Pharmacy Times, Volume 0, 0

Bupropion Extended-releaseTablets

The importance of patient adherencein successful treatment cannot be underestimated.Bupropion, initially developedfor the treatment of major depression,was first designed for multiple daily dosing,with later incarnations dosed twicedaily and, eventually, once daily. Beyondits initial indications, bupropion has alsodemonstrated effectiveness in depressionassociated with bipolar disorders, inadult attention-deficit disorders, in seasonalaffective disorder, and as a usefuladjunct in smoking-cessation programs.Bupropion is available in 150-and 300-mg tablets from Anchen Pharmaceuticals.

Pharmacology

Bupropion causes a weak inhibition ofthe natural uptake of norepinephrine,serotonin, and dopamine, with no effecton monoamine oxidase (MAO). Theactions on norepinephrine and dopamineare speculated to contribute to the activityof bupropion, and its extensivemetabolism by the CYP2D6 isoenzyme, aproperty shared with ~30% of otherdrugs, presents its greatest potential fordrug-drug interactions.

Administration

The once-daily formulation of bupropionis generally taken in the morning, witha 24-hour interval between doses. Intreating a major depressive disorder, thedosage is 1 150-mg extended-releasetablet, taken in the morning, which isthen increased to 300 mg once in themorning as soon as the 4th day. It shouldbe remembered that full therapeuticeffect may not be seen for as many as 4or more weeks. Occasionally, the dailydose may be further increased to 450mg; however, doses higher than this formajor depression are not recommended.

Safety Profile

At high daily doses, there is a risk forbupropion-induced seizures. A concurrenthistory of seizures increases therisk. The extended-release tablets appearto produce a lower occurrence of thiseffect than earlier formulations, a rate ofabout 0.1% to 0.4%.

To minimize seizure risk, daily doses ofextended-release bupropion should notexceed 450 mg. At least 2 weeks shouldelapse between the end of MAO inhibitortherapy and initiation of treatment withbupropion.

Due to its extensive hepatic metabolism,bupropion should be used with cautionin the presence of advanced cirrhosis.In addition, drugs metabolized by theCYP2D6 enzyme may demonstrate bloodlevel elevations with concurrent bupropionuse. These drugs include other antidepressants(nortriptyline, imipramine,desipramine, paroxetine, fluoxetine, sertraline);antipsychotics (haloperidol,risperidone, thioridazine); β-blockers;some antiarrhythmics (propafenone andflecainide); and analgesics (codeine andtramadol).

In theory, drugs inducing the 2B6enzyme (carbamazepine, phenobarbital,phenytoin) may also induce the metabolismof bupropion and diminish its effectiveness.Drugs that inhibit the 2B6enzyme, such as cimetidine, may potentiatebupropion toxicity too.

The effect of bupropion on weight isvariable: at 400 mg per day, one reportindicated that 19% of patients usingbupropion lost weight in excess of 5 lb(2% gained 5 lb or more). Althoughbupropion does not have weight loss asan indication, it is considered a noteworthyside effect when used as an antidepressantor a smoking-cessation aid.

Other side effects are primarily anticholinergicin nature (dry mouth, constipation);the 25% incidence of headachecompares with the 23% incidence thatoccurred with placebo. Just over 1/5 ofusers may experience an increase insweating while using bupropion.

Because bupropion has been availablein the past under 2 brand names withspecific target markets, pharmacistsshould be alert to the potential for duplicateprescriptions for the same activeingredient.

Outlook

As a unique agent, bupropion has anestablished record of effectiveness forthe treatment of depression, as well asother psychiatric conditions. In additionto the regular-release and sustained-releaseversions of bupropion, cliniciansnow have a 24-hour extended-releaseversion of the drug available in genericform for use by their patients. The once-dailydosing possible with this form ofbupropion offers added patient convenienceand a probable increase in therapeuticadherence.

Ondansetron Hydrochloride

The concept of allopathic medicine isbased on the exchange of one set of consequentialeffects for another. In theinstance of cancer treatment, the symptomsof the disease may range fromsilent to substantial. So it is with many ofthe current treatments for cancer. In theinterest of keeping the patient on schedulewith therapy, these therapeutic consequencesmust be addressed andsomehow minimized.

The profound nausea and vomiting followingmany standard chemotherapeuticprotocols has created a need fordrugs that selectively suppress type 3serotonin (5-hydroxytryptamine [5-HT3])receptors. These specialized drugs arenoteworthy both for their effect andexpense. Ondansetron liquid (4 mg/5 mL)is available from Roxane LaboratoriesInc. Ondansetron tablets are available instrengths of 4, 8, 16 , and 24 mg from DrReddy's Laboratories, and rapidly disintegratingtablets in the same strengths areavailable from Kali Laboratories Inc, awholly owned subsidiary of Par Pharmaceutical.FDA approval for the injectableform has been granted to Teva PharmaceuticalsUSA.

Pharmacology

The release of 5-HT3 from degenerativechanges in the gastrointestinal (GI)enterochromaffin cells is thought to be asignificant contributor to the nausea andvomiting associated with cisplatin andother chemotherapies. The releasedserotonin first stimulates vagal andsplanchnic nerve receptors, which thenproject to the emesis centers within themedulla. Specifically inhibiting the releaseof 5-HT3 is the accepted theory forthe effectiveness of ondansetron.

Administration

Ondansetron may be administeredorally as tablets, as rapidly disintegratingtablets, or in liquid form. An intravenous(IV) form is also available, and intramuscularadministration of the undilutedinjection is yet another option.

To treat moderate-emesis-producingchemotherapy, oral dosing for adults andchildren over 12 years old is 8 mg 30 minutesbefore treatment, followed by 8 mgat 12-hour intervals for 1 to 2 days followingtreatment. For protocols associatedwith high levels of emesis, a single 24-mg dose is given 30 minutes prior totreatment. Multiple daily doses of 24 mghave not been studied for enhancedeffectiveness.

IV use of ondansetron is often dosedby weight, at 0.15 mg/kg administeredover 15 minutes, starting 30 minutesprior to chemotherapy. This dose isrepeated at 4-hour intervals. As an alternative,a single, nonrepeated, 32-mgdose may be given as a 15-minute infusion30 minutes prior to chemotherapy.

There are other occasions besideschemotherapy when suppression of GI-basedserotonin effects may be useful aswell, including postoperative nausea andnausea associated with radiation therapy.For postoperative nausea, a single 4-mg IV dose of ondansetron is givenimmediately before the induction ofanesthesia, or postoperatively if symptomswarrant. For radiation-induced nauseaand vomiting, the usual oral dose is 8mg given 3 times daily.

Safety Profile

Ondansetron is generally well-tolerated.Headaches may occur in just under25% of patients.

The most common GI side effect associatedwith ondansetron therapy is diarrhea,occurring more often when it isadministered intravenously (8% to 16%)than orally (4% to 6%). This effect mayalso be due to the cancer chemotherapyitself, however, so a specific causal relationshiphas not been fully established.

Dosages should be reduced in hepaticfailure or disease, and patients should beaware that ondansetron may cause seriousallergic reactions on rare occasions.Also, incidences of liver damage in thecontext of concurrent chemotherapy arehard to directly associate with the use ofondansetron.

Ondansetron dosing does not need tobe adjusted for elderly patients. Patientswith phenylketonuria should also beaware that the rapidly dissolving tabletform of ondansetron contains the syntheticsweetener aspartame.

Outlook

The prevention of chemotherapy-inducednausea and emesis is almost asimportant as the treatment itself.Ondansetron, a selective and highlyeffective serotonin inhibitor, is now availablegenerically from several sourcesand in several forms to provide relief,more than in the GI sense.

Mr. Middleton is an instructor of pharmacologyat Kellogg CommunityCollege in Battle Creek, Mich.