Why Is the Trial Dose Not Available?

September 1, 2008
Albert Wertheimer, PhD, MBA

An important study demonstrated the efficacy of chlorthalidone for the treatmentof systolic hypertension in elderly persons,1 and the results have been validatedby other studies.

An important study demonstrated the efficacy of chlorthalidone for the treatment of systolic hypertension in elderly persons,1 and the results have been validated by other studies. The starting dosage of chlorthalidone in these trials, 12.5 mg/d, effectively controlled blood pressure in many patients. However, there is no 12.5-mg chlorthalidone tablet on the market. The pharmacy usually has to dispense 25-mg tablets, which must be cut in half. Often they crumble in the process.
I would think one of the manufacturers of generic formulations would offer a 12.5-mg tablet. Why is this not available?

-- Joseph Chersky, MD
Beverly Hills, Calif

 

This is a good question. Unfortunately, the answer does not hold much hope for an easy solution.

A manufacturer who proposes to market a generic version of an approved drug submits an Abbreviated New Drug Application (ANDA) to the FDA. The New Drug Application (NDA) of the original
(usually brand-name) drug would have been approved for specific formulations (eg, tablets or capsules) and for specific strengths, such as 25-mg and 50-mg tablets. The original NDA also would have contained data from several thousand persons who participated in the clinical trials, and it would have included bioavailability data.

An ANDA can be approved only when the manufacturer can demonstrate that the new (generic) tablet is within 10% of the bioavailability of the original product. Because no dosage in the original NDA for chlorthalidone was in the range of 12.5 mg, a potential manufacturer of a generic 12.5-mg tablet would have no NDA data to use for comparison. Nor would any generics manufacturer
invest in the trial required to submit a new NDA when it might only capture a small portion of the total 12.5-mg tablet market. Finally, the original manufacturer would not undertake a new clinical trial now, when most of the sales would go to manufacturers of cheaper generic products. Thus, we cannot expect to see a 12.5-mg formulation of chlorthalidone on the market.

However, there are some alternatives to splitting the 25-mg tablets. You might ask a nearby pharmacy to compound 12.5-mg capsules. Another option would be to ask the pharmacy to make a liquid formulation by dissolving either chlorthalidone powder or crushed tablets in a suitable liquid vehicle so that there would be 12.5 mg of the active ingredient in a teaspoonful of the liquid.

-- Albert Wertheimer, PhD, MBA
Professor of Pharmacy Temple University School of Pharmacy Philadelphia

References:

REFERENCE:


1

. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA. 1991;265:3255-3264.

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