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Jim Middleton, BS, RPh
Published Online: Thursday, February 1, 2007   [ Request Print ]

Bupropion Extended-release Tablets

The importance of patient adherence in successful treatment cannot be underestimated. Bupropion, initially developed for the treatment of major depression, was first designed for multiple daily dosing, with later incarnations dosed twice daily and, eventually, once daily. Beyond its initial indications, bupropion has also demonstrated effectiveness in depression associated with bipolar disorders, in adult attention-deficit disorders, in seasonal affective disorder, and as a useful adjunct in smoking-cessation programs. Bupropion is available in 150-and 300- mg tablets from Anchen Pharmaceuticals.

Pharmacology

Bupropion causes a weak inhibition of the natural uptake of norepinephrine, serotonin, and dopamine, with no effect on monoamine oxidase (MAO). The actions on norepinephrine and dopamine are speculated to contribute to the activity of bupropion, and its extensive metabolism by the CYP2D6 isoenzyme, a property shared with ~30% of other drugs, presents its greatest potential for drug-drug interactions.

Administration

The once-daily formulation of bupropion is generally taken in the morning, with a 24-hour interval between doses. In treating a major depressive disorder, the dosage is 1 150-mg extended-release tablet, taken in the morning, which is then increased to 300 mg once in the morning as soon as the 4th day. It should be remembered that full therapeutic effect may not be seen for as many as 4 or more weeks. Occasionally, the daily dose may be further increased to 450 mg; however, doses higher than this for major depression are not recommended.

Safety Profile

At high daily doses, there is a risk for bupropion-induced seizures. A concurrent history of seizures increases the risk. The extended-release tablets appear to produce a lower occurrence of this effect than earlier formulations, a rate of about 0.1% to 0.4%.

To minimize seizure risk, daily doses of extended-release bupropion should not exceed 450 mg. At least 2 weeks should elapse between the end of MAO inhibitor therapy and initiation of treatment with bupropion.

Due to its extensive hepatic metabolism, bupropion should be used with caution in the presence of advanced cirrhosis. In addition, drugs metabolized by the CYP2D6 enzyme may demonstrate blood level elevations with concurrent bupropion use. These drugs include other antidepressants (nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline); antipsychotics (haloperidol, risperidone, thioridazine); β-blockers; some antiarrhythmics (propafenone and flecainide); and analgesics (codeine and tramadol).

In theory, drugs inducing the 2B6 enzyme (carbamazepine, phenobarbital, phenytoin) may also induce the metabolism of bupropion and diminish its effectiveness. Drugs that inhibit the 2B6 enzyme, such as cimetidine, may potentiate bupropion toxicity too.

The effect of bupropion on weight is variable: at 400 mg per day, one report indicated that 19% of patients using bupropion lost weight in excess of 5 lb (2% gained 5 lb or more). Although bupropion does not have weight loss as an indication, it is considered a noteworthy side effect when used as an antidepressant or a smoking-cessation aid.

Other side effects are primarily anticholinergic in nature (dry mouth, constipation); the 25% incidence of headache compares with the 23% incidence that occurred with placebo. Just over 1/5 of users may experience an increase in sweating while using bupropion.

Because bupropion has been available in the past under 2 brand names with specific target markets, pharmacists should be alert to the potential for duplicate prescriptions for the same active ingredient.

Outlook

As a unique agent, bupropion has an established record of effectiveness for the treatment of depression, as well as other psychiatric conditions. In addition to the regular-release and sustained-release versions of bupropion, clinicians now have a 24-hour extended-release version of the drug available in generic form for use by their patients. The once-daily dosing possible with this form of bupropion offers added patient convenience and a probable increase in therapeutic adherence.


Ondansetron Hydrochloride

The concept of allopathic medicine is based on the exchange of one set of consequential effects for another. In the instance of cancer treatment, the symptoms of the disease may range from silent to substantial. So it is with many of the current treatments for cancer. In the interest of keeping the patient on schedule with therapy, these therapeutic consequences must be addressed and somehow minimized.

The profound nausea and vomiting following many standard chemotherapeutic protocols has created a need for drugs that selectively suppress type 3 serotonin (5-hydroxytryptamine [5-HT3]) receptors. These specialized drugs are noteworthy both for their effect and expense. Ondansetron liquid (4 mg/5 mL) is available from Roxane Laboratories Inc. Ondansetron tablets are available in strengths of 4, 8, 16 , and 24 mg from Dr Reddy's Laboratories, and rapidly disintegrating tablets in the same strengths are available from Kali Laboratories Inc, a wholly owned subsidiary of Par Pharmaceutical. FDA approval for the injectable form has been granted to Teva Pharmaceuticals USA.

Pharmacology

The release of 5-HT3 from degenerative changes in the gastrointestinal (GI) enterochromaffin cells is thought to be a significant contributor to the nausea and vomiting associated with cisplatin and other chemotherapies. The released serotonin first stimulates vagal and splanchnic nerve receptors, which then project to the emesis centers within the medulla. Specifically inhibiting the release of 5-HT3 is the accepted theory for the effectiveness of ondansetron.

Administration

Ondansetron may be administered orally as tablets, as rapidly disintegrating tablets, or in liquid form. An intravenous (IV) form is also available, and intramuscular administration of the undiluted injection is yet another option.

To treat moderate-emesis-producing chemotherapy, oral dosing for adults and children over 12 years old is 8 mg 30 minutes before treatment, followed by 8 mg at 12-hour intervals for 1 to 2 days following treatment. For protocols associated with high levels of emesis, a single 24- mg dose is given 30 minutes prior to treatment. Multiple daily doses of 24 mg have not been studied for enhanced effectiveness.

IV use of ondansetron is often dosed by weight, at 0.15 mg/kg administered over 15 minutes, starting 30 minutes prior to chemotherapy. This dose is repeated at 4-hour intervals. As an alternative, a single, nonrepeated, 32-mg dose may be given as a 15-minute infusion 30 minutes prior to chemotherapy.

There are other occasions besides chemotherapy when suppression of GI-based serotonin effects may be useful as well, including postoperative nausea and nausea associated with radiation therapy. For postoperative nausea, a single 4- mg IV dose of ondansetron is given immediately before the induction of anesthesia, or postoperatively if symptoms warrant. For radiation-induced nausea and vomiting, the usual oral dose is 8 mg given 3 times daily.

Safety Profile

Ondansetron is generally well-tolerated. Headaches may occur in just under 25% of patients.

The most common GI side effect associated with ondansetron therapy is diarrhea, occurring more often when it is administered intravenously (8% to 16%) than orally (4% to 6%). This effect may also be due to the cancer chemotherapy itself, however, so a specific causal relationship has not been fully established.

Dosages should be reduced in hepatic failure or disease, and patients should be aware that ondansetron may cause serious allergic reactions on rare occasions. Also, incidences of liver damage in the context of concurrent chemotherapy are hard to directly associate with the use of ondansetron.

Ondansetron dosing does not need to be adjusted for elderly patients. Patients with phenylketonuria should also be aware that the rapidly dissolving tablet form of ondansetron contains the synthetic sweetener aspartame.

Outlook

The prevention of chemotherapy-induced nausea and emesis is almost as important as the treatment itself. Ondansetron, a selective and highly effective serotonin inhibitor, is now available generically from several sources and in several forms to provide relief, more than in the GI sense.

Mr. Middleton is an instructor of pharmacology at Kellogg Community College in Battle Creek, Mich.


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