FDA SAFETY PAGE

A look at delayed- vs. extended-release Rxs

Carol Holquist, R.Ph., and Walter Fava, R.Ph. The United States Pharmacopeia (USP) defines delayed-
release tablets as enteric-coated to delay release of the med­
harmaceutical manufacturers often create new dosage ication until the tablet has passed through the stomach to
P formulations of the same active ingredient. Are you prevent the drug from being destroyed or inactivated by
aware of the implications of these sometimes subtle differ­ gastric juices or where it may irritate the gastric mucosa.
ences? How many times have you used the terms delayed- USP defines extended-release tablets “formulated in such a
release and extended-release interchangeably? Many Food & manner to make the contained medicament available over
Drug Administration-approved drugs are available in an extended period of time following ingestion.” Both the
multiple product formulations—immediate-release, de- delayed-release and extended-release formulations of De­
layed-release, and extended-release. Although they con­ pakote are enteric-coated but not interchangeable.
tain the same active ingredient and are available in identi­ Pharmacokinetic studies have shown that when De­
cal strengths, they are not bioequivalent. So it is important pakote ER is given in equal total daily doses, its bioavail­
for practitioners to recognize these differences to ensure ability is approximately 10% less than that of the delayed-
the correct product formulation and dose are dispensed. release tablets. Thus, an equivalent dose of either dosage
Depakote (divalproex sodium) is an example of such form does not provide an equivalent pharmacokinetic
product-line extension. It is available as delayed-release profile. Product confusion may therefore result in signifi­
cant clinical effects in patients.
Product(s)/strength Formulation FDA approval date Asked what contributed to
the product confusion, almost
Depakote 250 mg, 500 mg Enteric-coated delayed-release 1983
all reporters said they never
Depakote 125 mg Enteric-coated delayed-release 1984 knew there was a difference
between delayed-release and
Depakote 125 mg Sprinkle delayed-release 1989 extended-release dosage for­
mulations and did not know
Depakote ER 250 mg, 500 mg Enteric-coated extended-release 2002 of the introduction of the new
extended-release formulation.
capsules (Depakote Sprinkles), enteric-coated delayed- Other contributing factors included the sound-alike
release tablets (Depakote), and enteric-coated extended- names Depakote ER (extended-release) and Depakote DR
release tablets (Depakote ER). Several medication error re­ (delayed-release), visual similarities in the unit-dose pack­
ports have been received over the past several years which aging, and computer entry errors due to the overlapping
indicate a lack of understanding of the product differences portion of established names (divalproex sodium), and
between the different formulations of Depakote. overlapping product strengths (250 mg and 500 mg).
In 2004, FDA received two medication error reports It is important for practitioners to understand the phar­
about institutions making formulary decisions based sole­ macokinetic differences for each formulation of Depakote,
ly on frequency of dosing without considering the inher­ and to implement strategies to minimize the potential un­
ent pharmacokinetic differences between the delayed- wanted outcomes and errors. Strategies might include
release and extended-release formulations. Another re­ clearly marking the shelves where Depakote delayed-
port, in 2005, documented hospital personnel crushing release and Depakote extended-release products are
Depakote tablets prior to giving them to a patient. A 2006 stored, to make them more distinguishable—especially
medication error report documented the reporter, a phar­ since they are stored adjacent to each other. Also consider
macist, using delayed-release and extended-release inter­ highlighting or flagging the different Depakote products
changeably. Also in 2006, FDA received a medication error in computer menus so that each formulation has a differ­
report that documented a hospital pharmacy defining De­ ent appearance to decrease computer selection errors. Fi­
pakote delayed-release tablets as the “twice-a-day” formu­ nally, educate the pharmacy staff on the product differ­
lation, and Depakote ER as the “once-a-day” formulation. ences so that knowledge deficits will not contribute to
Thus, when a patient was admitted taking Depakote ER Depakote errors in the future.
750 mg twice a day for seizure control, the pharmacy in­ CAROL HOLQUIST is Director and WALTER FAVA is Safety Evaluator in the Division
of Medication Errors and Technical Support, The Office of Surveillance and
correctly dispensed Depakote delayed-release tablets. Epidemiology at the Food & Drug Administration.

56 DRUG TOPICS JULY 23 2007 www.drugtopics.com