# [Medical/IDS Review]{.underline}

**NDA \# : 19-658**

**Drug Name: Claritin 24 (Loratadine)**

**Sponsor: Schering-Plough**

**Subject: CIU Self-Recognition and Label Comprehension Study**

**Reviewer: Linda Hu, M.D.**

**Matthew Holman, Ph.D.**

**Date: March 26, 2002**

This label comprehension study was designed to evaluate Claritin ® 24
for over-the-counter (OTC) treatment of chronic idiopathic urticaria
(CIU). Claritin ® 24 (loratadine) is currently a prescription medication
prescribed for the treatment of seasonal allergic rhinitis and chronic
idiopathic urticaria. Currently CIU is not an OTC indication for any
product marketed in the U.S. The label study was designed to evaluate
whether consumers can understand label directions, and in particular the
new indication and direction for previously diagnosed, recurring or
chronic hives. This review did not examine the entire Label
Comprehension Study, but focused on issues that will likely be discussed
at the Advisory Committee meeting.

The **objectives** of this study were to evaluate if consumers:

-   understand the uses, directions and warnings as based on reading the
    product label

-   can accurately self-recognize CIU upon recurrence and appropriately
    self-select Claritin for use

[Study Design]{.underline}

This was an all-comers study enriched with several special populations.
Twenty-four marketing research facilities located in twenty-one
geographically dispersed markets across the United States were used to
complete recruiting and enrollment for this study. Subjects were
recruited through advertising, direct mail, and mall intercept for
participation. Qualified subjects were asked to read a product label and
package insert for Claritin 24 and then were interviewed and asked
questions to determine their understanding. Subjects were told that they
would be able to refer to the label as needed.

A total of 565 subjects were interviewed for this study. Five study
cohorts were defined as follows:

1\) Cohort 1: Self-recognized CIU sufferers (N=196) who indicate that
they have been previously diagnosed by a physician as having the
condition;

2)  Cohort 2: General population (N=116)

3)  Cohort 3: Low Literacy (N=96)

4)  Cohort 4: Special cohort who should according to the label "Ask a
    doctor before use", such as those who have liver, kidney disease,
    are pregnant, or are nursing/breast feeding (N=114)

5)  Cohort 5: Special cohort with a history of hives who did not have a
    diagnosis of chronic hives or CIU by a physician (N=102); this was
    the acute hive cohort.

Subjects with CIU (Cohort 1) were recruited by first being asked if they
had any of a list of health conditions. If they answered they had hives,
they were asked \"Has a doctor ever told you that you have recurring or
chronic hives with an unknown cause, also known as Chronic Idiopathic
Urticaria (CIU)?\" If they answered affirmatively, they qualified for
Cohort 1. If they answered negatively, they qualified for the acute hive
group (Cohort 5).

Key label communication objectives were as follows:

-   Claritin relieves and reduces itching and rash due to recurring or
    chronic hives of an unknown source (CIU)

-   Claritin should be used only after being diagnosed by a doctor for
    recurrent or chronic hives

-   The consumer should seek emergency medical attention (if rash,
    hives, insect bite or sting are accompanied with trouble swallowing,
    fever above 100º F, wheezing or problems breathing, hives or
    swelling in or around mouth, drooling, trouble speaking, or joint
    pain); warnings not to use if allergic to loratadine or other
    antihistamines; and warnings not to use for hives unless previously
    diagnosed with CIU by a physician and not to use for food allergies
    or insect bites and stings.

-   This product should not be used to treat food allergies or insect
    bites or stings

[Label Comprehension]{.underline}

Label comprehension was assessed by asking both direct and
scenario-based questions. First, the participants were asked directly,
as an open-ended question (Q1), what the product was used for, and in
addition, another question (Q2) as to whether Claritin was intended for
use in any of several listed conditions. Second, a series of scenarios
was presented, and participants were asked whether Claritin is intended
to be used in the scenario described. For Cohorts 1, 2, 3, and 5, some
of the scenarios reflected actual sufferers of CIU. Subjects in Cohort 4
answered a shortened questionnaire to test if they understood that they
should ask a doctor before use.

[Self-Selection]{.underline}

The label comprehension study questionnaire also included questions
relating to "self-selection". The purpose of this question was to
determine if consumers understood whether they *personally* could use
Claritin. Because the intent of Cohort 4 was to determine if subjects
with liver/kidney/pregnancy/nursing recognized that they should ask a
doctor prior to use, these subjects were asked to assume they had been
told by their doctor that they have recurring hives or hives of an
unknown source.

As a follow-up to the self-selection question, all cohorts were asked to
state reason(s) for their answer. To ascertain whether participants
answered correctly regarding self-selection, they were asked a series of
medical history/health questions that determined if they had been
diagnosed with CIU, had chronic hives, or had contraindications to use.

[Self-Recognition]{.underline}

Subjects in Cohort 1 (self-recognized CIU group) were assessed for
accurate self-recognition based on a follow-up discussion with a study
physician. This assessment was based on a discussion between the subject
and the study physician regarding the subject\'s medical history, and in
some cases, subject's selection of a photograph that best represented
their skin lesions when they experienced CIU. In other cases, those
currently experiencing hives had their hives photographed. In many
cases, the photographs of subjects' lesions were of poor quality and
were not usable.

[Demographics]{.underline}

The demographics of the five study cohorts are summarized in Table 1. An
individual participant could be assigned to more than one cohort, so the
sum of all cohort totals exceeds the total number of study participants.
Two-thirds of the participants were female.

Table 1 Study Populations

  --------------------------- ----------- --------------- ----------------
  Cohort                      Male        Female          Total

  CIU                         49          147             196

  General Population          44          72              116

  Low Literacy                38          58              96

  Contraindicated             47          67              114

  Acute Urticaria             35          67              102

  **Total**                   193         372             565
  --------------------------- ----------- --------------- ----------------

The income distribution of the participants in the study cohorts is
given in Table 2. The Low Literacy cohort had a significantly higher
proportion of subjects in the lowest annual income group, \< \$15K. The
CIU cohort had a significantly higher proportion of members in the
highest income group (\>\$75 K annually) than all the other cohorts.

Table 2 Annual Income distribution

  ----------------- ------- --------- --------- --------- --------- ------- ------------
                    \<15K   15K-25K   25K-35K   35K-45K   50K-75K   \>75K   Total
                                                                            Responding

  CIU               16      22        25        38        45        43      196

  General           13      20        21        23        19        15      116
  Population                                                                

  Low Literacy      29      20        22        17        3         3       96

  Contraindicated   16      19        20        21        19        13      112

  Acute Urticaria   12      13        24        25        14        11      102

  **Total**         74      85        101       116       93        76      563
  ----------------- ------- --------- --------- --------- --------- ------- ------------

The age distributions of the participants in the study cohorts is given
in Table 3. The CIU group had an older population than the general
population cohort and the acute urticaria cohort.

Table 3 Age Distribution

  ----------------- ------- ------- ------- ------- ------- -----------------
                    18-34   35-44   45-54   55-64   \> 65   Total Responding

  CIU               45      47      62      28      14      196

  General           62      19      18      13      4       116
  Population                                                

  Low Literacy      32      34      16      10      4       96

  Contraindicated   35      22      27      13      17      114

  Acute Urticaria   42      23      16      11      10      102

  **Total**         190     132     126     70      47      565
  ----------------- ------- ------- ------- ------- ------- -----------------

##### RESULTS 

[Label Comprehension]{.underline}

### Consumer understanding of the product uses was tested by questions 1 and 2 (Q1 and Q2). To be considered "correct", responders had to state specifically that CIU or recurring/chronic hives, not just hives, was the intended use for the product. Answers were considered "acceptable" if respiratory allergies, hay fever, or allergic rhinitis were mentioned along with CIU since Claritin has been used extensively for this indication. Note, however, that these indications were not listed on the label presented to these consumers in this study. Answers were considered "incorrect" for those who mentioned CIU along with an incorrect product use, such as for colds/flu, other allergic reactions or if just hives in general were mentioned. 

Table 4 summarizes the correct and acceptable response rate to these
direct questions and several pertinent scenarios relating to product use
across the different cohorts.

Table 4. Product Use -- whether consumers understand uses of Claritin (%
Correct/Acceptable) ![](media/image1.png)

\*The proportions/means are compared for statistically significant
differences at the 95% confidence level. A lower case letter next to the
percent indicates a value significantly greater than the value in the
corresponding column.

**Question 1** *Based on the label, what is this product used for?*
(open-ended question)

When asked on an open-ended basis what the product was used for, CIU
sufferers demonstrated the strongest understanding (77%
correct/acceptable). The correct/acceptable response rates for the other
cohorts ranged from 49% to 58%. The most common incorrect answer
(mentioned by 20% of the total number of subjects ) was hives/rash
(because the subject did not specify that the hives were chronic). This
percentage was 30-~~4~~0% among the acute hive cohort, depending on how
individual responses are classified. It is difficult to elicit specific
answers such as chronic hives or hives of an unknown source with an
open-ended question. Other common incorrect mentions were "allergies" in
general or hay fever. There were also several mentions of asthma,
cold/flu, trouble speaking/swallowing, drooling, fever, and joint pain.

**Question 2** *Is this product intended to be used for the following
conditions? (Ear infections, hay fever, colds, sinus infections, upper
respiratory allergies, food allergies, insect bites/stings, a one time
breakout of hives, allergies to animal/pets, recurring or chronic hives
of an unknown* *cause)*

CIU sufferers in Cohort 1 scored the highest (71% correct) for this
question, with the other cohorts answering correctly in only 38%-49%.
However, for to be considered correct for Q2, the subject had to answer
correctly for all conditions listed above.

Table 5 lists the number that responded "yes" to this question for each
of the previous conditions. In all cohorts combined, 92% of subjects
stated this product was intended for use in recurring or chronic hives
of an unknown cause, but not all were considered "correct/acceptable"
for Q2 because they also stated it is indicated for other incorrect
conditions. The highest proportion (71%) gave the correct response, in
the CIU cohort.

When the conditions were examined separately, nearly one-quarter (22%)
of all participants stated that the product was intended for hay fever,
and 18% thought the product could be used for insect bites/stings.
Forty-two percent of the general population cohort, 44% of the acute
hive cohort, and 20% of the CIU cohort thought that the product could be
used for a one time breakout of hives.

For the general population cohort, 39% thought the product was intended
for hay fever, 11% for colds, 16% for food allergies, 27% for insect
bites/stings, 29% for allergies to animals/pets and 85% for recurring or
chronic hives of an unknown cause.

Table 5. (Question 2) Is the product intended to be used for following
conditions: (those answering yes)

  -------------------------- ----------- --------- ------- -------- ----------------------- ---------
                             **Total**   **CIU**   **Gen   **LL**   **Preg/Liver/Kidney**   **Acute
                                                   Pop**                                    Hives**

  Total Responding           565         196       116     96       114                     102

  Ear Infections             1.9%        \--       1.7%    8.3%     0.9%                    2.0%

  Hay Fever                  21.6%       11.7%     38.8%   22.9%    16.7%                   35.3%

  Colds                      7.6%        0.5%      11.2%   15.6%    4.4%                    18.6%

  Sinus Infections           9.2%        1.0%      17.2%   13.5%    7.0%                    17.6%

  Upper Respiratory          18.1%       8.2%      31.0%   16.7%    13.2%                   33.3%
  Allergies                                                                                 

  Food Allergies             11.7%       7.1%      16.4%   13.5%    13.2%                   20.6%

  Insect Bites/Stings        18.4%       9.2%      26.7%   18.8%    23.7%                   29.4%

  One Time Breakout of Hives 32.0%       19.9%     42.2%   36.5%    37.7%                   44.1%

  Allergies to Animals/Pets  17.7%       9.7%      29.3%   21.9%    14.0%                   31.4%

  Recurring or Chronic Hives 91.7%       99.0%     85.3%   84.4%    89.5%                   92.2%
  of an Unknown Cause                                                                       
  -------------------------- ----------- --------- ------- -------- ----------------------- ---------

A series of scenarios was also presented to study participants. These
questions and the percent correct in each cohort is also summarized in
Table 4. The scenarios from this table are provided in their entirety as
follows.

**Scenario B** "Jane is allergic to peanuts, and she accidentally ate a
candy bar that had peanuts in it. Her arms have broken out into hives.
Her tongue has started to swell and it is getting hard for her to
swallow. She wants to take something to help her."

"Based on the label, is this product intended to be used for this
situation, or not?"

**Scenario C** "Pam was working in the garden and got stung by a bee.
She suddenly developed a rash and is having trouble breathing."

"Based on the label, is this product intended to be used for this
situation, or not?"

**Scenario D** "For the past several months, Ted has broken out in hives
about every week. His doctor told him he has a condition called "Chronic
Idiopathic Urticaria" or recurrent hives of an unknown source or no
known cause."

"Based on the label, is this product intended to be used for this
situation, or not?"

**Scenario E** "Bill is on a hiking trip through the woods and developed
an itchy red rash on his legs. He wants to take something to relieve his
symptoms"

"Based on the label, is this product intended to be used for this
situation, or not?"

**Scenario G** "Sue broke out in hives on her arms and legs for the
first time in her life. She would like to take a product to treat the
hives."

"Based on the label, is this product intended to be used for this
situation, or not?"

[Self-Selection]{.underline}

##### Questions (Q17/18) *Considering everything on the package label, is this product intended for you, [personally]{.underline}, to take home and start using? Why do you say that?*

The purpose of the \"self-selection\" series of questions was to
determine if consumers understood whether they *personally* could use
Claritin based on their personal history of hives, as well as their
current medications and medical conditions. Using this information, the
Sponsor classified subjects as belonging to one of three categories: "OK
to use", "Ask a doctor first", and "Do not use".

For the self-selection question, a high proportion of previously
diagnosed CIU sufferers (Cohort 1) gave correct or acceptable answers
(Table 6). However, a significant proportion of those in the general
population (Cohort 2) and acute hive population (Cohort 5), 30% and 46%
respectively, gave incorrect responses.

Table 6. Self-Selection Question (Q17/18)
![](media/image2.png){width="5.99375in" height="2.5791666666666666in"}

In the general population (Cohort 2), the large majority of whose
members should not use, there were 73 correct or acceptable answers from
104 responding (70%) in the group. Of those in Cohort 2 who should ask a
doctor first, 7/8 (87%) answered correctly or acceptably, while all of
those who evaluated as OK to use did self-select to use, 4/4 (100%). The
fraction of general population participants who decided correctly not to
use is marginal. Of those who answered incorrectly, 19% stated the
product was intended for allergic rhinitis or allergies, 19% stated it
relieved itching/rash, 16% stated it relieved hives, and 9% said it
relieved chronic/recurrent hives.

In the acute urticaria group (cohort 5) who should not use or should ask
a doctor, 55/102 (54%) gave correct or acceptable answers. They stated
that the product was not intended for their use or that they would "ask
their doctor" prior to use. This is a low percentage of correct answers.
Of those who answered incorrectly, at least 23% stated that the product
could be used to relieve hives, 21% stated the drug relieves
chronic/recurring hives, 15% stated relieves itching/rash, and 11%
responded that the product can be taken for allergies or allergic
rhinitis. The respondents that answered the product is intended to treat
chronic/recurring hives did not have a physician diagnosis of CIU
(although this is not explicitly stated in the submission).

The results of this question indicate that 46% of consumers with acute
urticaria will incorrectly decide to self-treat with Claritin. Of
consumers in the general population who should not use, about 30% will
self-select to use the drug.

[Self-Recognition]{.underline}

Only subjects in Cohort 1, CIU Sufferers (self-reported), participated
in this arm of the study. In order for the subjects to be evaluated on
the ability to self-recognize chronic idiopathic urticaria, they spoke
with a nurse and a study physician at West™s Central Medical Operations
Group (CMOG). Nearly all of the subjects (94%) who self-reported having
CIU were confirmed by the physician as having CIU.

### **DISCUSSION**

The study results suggest that over 90% of consumers with a previous
diagnosis of CIU, about 30% of consumers from the general population
without a previous diagnosis, and about 46% of those with acute hives
believe that the product is intended for their use. Incorrect reasons
for self-selecting to use the drug included: the product was to be used
for hives without specifying chronic, acute hives, allergic rhinitis,
itching/rash, or chronic/recurrent hives without a prior physician
diagnosis. There were also several mentions of asthma, cold/flu, trouble
speaking/swallowing, drooling, fever, and joint pain. Question 2 showed
that in the general population cohort, 39% thought the product was
intended for hay fever, 11% for colds, 16% for food allergies, 27% for
insect bites/stings, 42% for a one time break out of hives, 29% for
allergies to animals/pets.

The study suggests that some consumers who do not have a prior diagnosis
of CIU will not make the distinction between general hives, acute hives,
and chronic urticaria when deciding whether this product may be right
for them to use. Others will use for generally accepted indications for
Claritin. An important issue is whether consumers with symptoms of
anaphylaxis recognize that they should seek immediate medical attention.
Although study participants were shown scenarios describing anaphylaxis,
they were not asked specifically whether or when to seek medical
attention.

\* The Agency has asked the Sponsor to further categorize, summarize and
quantify responses to some questions since results were primarily
presented as raw data