Safety Page
`Kaopectate reformulation and upcoming labeling changes
`atric dosing instructions are
`describe the potential for medica-
`The Food & Drug Administra-
`depleted, all three formulations
`tion errors due to its reformulation
`tion wants to alert healthcare
`may be stored near each other in
`as a salicylate, concerns over the
`providers to formulation changes
`the pharmacy and possibly be con-
`lack of promotion and education on
`that have occurred with Kaopec-
`fused.
`the new formulation, inadequate
`tate and the potential for con-
`labeling, and packaging of the
`sumers to confuse the multiple
`newly formulated Kaopectate.
`available formulations and dosing
`According to the reporters, the
`instructions under this product
`sponsor did not adequately inform
`name. The current Kaopectate
`healthcare providers and patients of
`marketed is not the formulation
`this important reformulation.
`you remember with Kaolin and
`Pectin. In the late 1980s
`or early ’90s, the manu-
`facturer reformulated
`the product to contain
`attapulgite. Then in
`2003, the sponsor refor-
`mulated the product
`again, this time to in-
`clude bismuth subsali-
`cylate as the active
`ingredient. Following
`this 2003 reformulation,
`the FDA received six medication
`error reports involving confusion
`over the “new and improved”
`Kaopectate.
`Two reports involved errors in
`product purchase. In one case, an
`emergency physician prescribed
`Kaopectate for a very young child.
`In talking with the mother of the
`child, the pharmacist found that
`the child also had a fever. The
`pharmacist called the physician to
`advise him of the change in for-
`mulation, and the physician
`directed the pharmacist not to fill
`the prescription for the child. A
`report of the second case describes
`several consumers who returned
`the new Kaopectate because, upon
`reading the label, they realized
`that it was not appropriate for
`them. Neither of the reports noted
`any patient harm, as the errors
`were intercepted before reaching
`the patient.
`The remaining four medication
`error reports for Kaopectate
`
`Why the formulation change?
`In 2003, the active ingredient in
`Kaopectate was reformulated to
`contain bismuth subsalicylate,
`replacing attapulgite as the ac-
`tive ingredient. The FDA
`found attapulgite efficacy
`data to be inadequate and,
`thus, attapulgite was not
`included as a monograph
`ingredient in the April 17,
`2003, final rule. Only bis-
`muth subsalicylate and
`kaolin are generally recog-
`nized as safe and effective
`as OTC antidiarrheal
`drugs in the final rule.
`Moreover, in the changes of the
`April 17, 2003, final rule, bismuth
`subsalicylate may only be labeled
`for adults and children 12 years and
`over because data are needed to
`support use in children under 12
`years of age.
`
`What are the safety concerns?
`In light of the formulation changes
`that have already occurred and the
`future labeling changes with Kao-
`pectate, there are several important
`factors to be considered by healthcare
`practitioners to appropriately alert
`and educate unwary consumers.
`
`•Fomulation change confusion
`The sponsor, Pharmacia Consumer
`Healthcare, notes that the older for-
`mulation of Kaopectate with atta-
`pulgite will remain in stores until
`sold. Thus, stores will likely have
`both formulations of Kaopectate on
`their shelves. A consumer not real-
`izing the formulation change may
`unknowingly grab the new bottle,
`
`Original
`Kaopectate
`(Attapulgite)
`750 mg/15mL
`
`3 to 6 years
`6 to 12 years
`12 years and over
`
`Dose: Take first dose at
`first sign of diarrhea and
`after each subsequent bowel
`movement. Maximum six
`times in 24 hours
`1/2 tablespoonful (7.5 mL)
`1 tablespoonful (15 mL)
`2 tablespoonfuls (30 mL)
`
`Lastly, the currently marketed
`“new and improved” formulation
`with bismuth subsalicylate not
`only contains a salicylate, it also
`has dosing instructions for chil-
`dren under 12 years of age. Salicy-
`lates are not generally recom-
`mended for children because of
`risks of Reye’s syndrome, salicy-
`late allergy, and salicylate over-
`dosage. To further confuse mat-
`ters, according to the final FDA
`rule on antidiarrheal monograph,
`effective April 17, 2004, bismuth
`subsalicylate will no longer be
`labeled with pediatric dosing
`instructions. Until existing sup-
`plies of the attapulgite and subsal-
`icylate product labeled with pedi-
`
`By
`Linda Y. Kim-Jung, R.Ph.;
`Carol Holquist, R.Ph.;
`and Jerry Phillips, R.Ph.
`
`To report a problem with an FDA-regulated product, please call 1-800-FDA-1088.
`
`58
`
`DRUG TOPICS APRIL 19 2004
`
`www.drugtopics.com
`
`ALKERMES EXHIBIT 2048
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`Page 1 of 2
`
`

`

`Safety Page
`
`ble pediatric dosing errors which
`may occur due to the formulation
`change and the labeling change
`with Kaopectate.
`A consumer not realizing the
`formulation change from atta-
`pulgite to bismuth subsalicylate
`may unknowingly grab the new
`bottle, and give a child a larger
`dose than required, thinking that
`the product is still the old Kaopec-
`tate with attapulgite. For example,
`a six-year-old child’s dose is one
`tablespoonful (15 mL) for the Kao-
`pectate with attapulgite, whereas
`the dose is two teaspoonfuls (10
`mL) for Kaopectate with bismuth
`subsalicylate. See tables (page 58
`and below) for the different
`
`and ingest a salicylate-containing
`product. Although the new formu-
`lation contains a salicylate warning
`statement on the label, it is not
`prominent and could be easily
`overlooked. This could lead to seri-
`ous medical consequences such as
`Reye’s syndrome, salicylate allergy,
`and salicylate overdosage. Like
`aspirin, bismuth subsalicylate prod-
`ucts could potentially have many
`drug-to-drug and drug-to-disease
`interactions.
`For example, bismuth subsalicy-
`late could have interactions with
`anticoagulants, hypoglycemic
`agents, and nonsteroidal anti-
`inflammatory drugs (NSAIDs)
`and other anti-inflammatory med-
`ications. Medical condi-
`tions such as gout, stom-
`ach ulcer, kidney dis-
`ease, and bleeding prob-
`lems could become more
`problematic with the use
`of a salicylate-containing
`product. A medical sce-
`nario was published in
`the ISMP Medication
`Safety Alert (March 20,
`2003). “Bismuth Subsali-
`cylate also can lead to darkened or
`black-colored stools. A patient
`reporting this finding might be mis-
`diagnosed with sustained gastroin-
`testinal bleeding if the practitioner
`is unaware of the change in formu-
`lation.”
`
`•Confusion with pediatric dosing
`Following the final rule’s effective
`date of April 19, 2004, bismuth sub-
`salicylate may only be labeled for
`adults and children 12 years and
`over. However, products that are
`already in the store (i.e., with labeling
`for children under 12 years old) can
`continue to be sold, as there will not
`be a recall. As a result, there will be
`two versions of the newly formulated
`Kaopectate with different pediatric
`dosing requirements, which may fur-
`ther confuse healthcare practitioners
`and consumers.
`Here are two examples of possi-
`
`60
`
`DRUG TOPICS APRIL 19 2004
`
`effects. The current label contains
`information to convey the change
`in active ingredient but this infor-
`mation is subtle and can easily be
`overlooked.
`•Be aware that, potentially, there
`may be three versions of Kaopectate
`on the pharmacy shelf: One version
`of Kaopectate with attapulgite, a sec-
`ond version of Kaopectate with bis-
`muth subsalicylate (with pediatric
`dosing instructions), and a third ver-
`sion of Kaopectate with bismuth sub-
`salicylate without pediatric dosing.
`•Provide shelf talkers or some
`other visual aid to alert consumers
`about the change in ingredient. For
`example, the shelf talker might say,
`“This product has been reformulat-
`ed and now contains a
`Salicylate, a new active
`ingredient. If you have
`questions, talk to the
`Pharmacist.” In addition,
`physically separate the
`different formulations to
`minimize potential con-
`fusion for consumers.
`•Advise patients not to
`remove the back panel
`peel-up label, which
`contains all the Drug Facts. The
`peel-up label could easily tear or
`be removed and discarded. This is
`problematic as the peel-up label
`contains the drug warnings,
`dosage directions, detailed salicy-
`late warnings, lot number, and
`expiration date.
`If you become aware of medica-
`tion errors involving Kaopectate
`or other products, please report
`them to the FDA MedWatch pro-
`gram at www.fda.gov/medwatch.
`In addition, medication errors can
`be reported to the USP Medication
`Errors Reporting Program in coop-
`eration with the Institute for Safe
`Medication Practices at 1-800-23-
`ERROR or at www.usp.org.
`
`Linda Y. Kim-Jung is a Safety Evaluator; Carol
`Holquist is the Deputy Director of the Division of
`Medication Errors and Technical Support; and Jerry
`Phillips is the Associate Director for Medication Error
`Prevention, Office of Drug Safety, at the Food & Drug
`Administration.
`
`www.drugtopics.com
`
`New & improved
`Kaopectate
`(Bismuth subsalicylate)
`262 mg/15 mL
`Three to five years
`Six to eight years
`9 to 11 years
`12 years and over
`
`Dose: Repeat dose every
`1/2 hour-1 hour as needed,
`to a maximum of eight doses
`in a 24-hour period.
`1 teaspoonful (5 mL)
`2 teaspoonfuls (10 mL)
`1 tablespoonful (15 mL)
`2 tablespoonfuls (30 mL)
`
`dosage recommendations between
`the original and new Kaopectate.
`Secondly, consumers will likely
`get mixed dosing information
`because one version of Kaopectate
`with subsalicylate states that it is
`appropriate for children under 12
`years of age and yet another ver-
`sion of Kaopectate with bismuth
`subsalicylate is not labeled for
`children under 12 years of age.
`Based on the old product with
`attapulgite and the bismuth sub-
`salicylate with pediatric dosing
`labels, consumers may still give
`the product to children under 12
`or at an inappropriately high dose,
`which may result in harm.
`In order to avoid confusion with
`the new formulation and the pro-
`duct’s labeling changes, here are
`some measures pharmacists can take:
`•Be aware of the new active ingre-
`dient and its potential adverse
`
`Page 2 of 2
`
`