**SPL Release 2 Implementation Guide for Highlights**

[1. Introduction 1](#introduction)

[2. Stylesheet and Schema 1](#stylesheet-and-schema)

[3. FPI Sections and Subsections 2](#fpi-sections-and-subsections)

[4. Recent Major Changes in FPI Text
2](#recent-major-changes-in-fpi-text)

[5. Adverse Drug Reaction Reporting Information
2](#adverse-drug-reaction-reporting-information)

[6. Year of Initial US Approval 3](#year-of-initial-us-approval)

[7. Highlights Text 4](#highlights-text)

[8. Indications 5](#indications)

[9. Maximum Dose 7](#maximum-dose)

[10. Condition of Use 8](#condition-of-use)

[11. Limitation of Use 11](#limitation-of-use)

[12. Drug Interaction 12](#drug-interaction)

[13. Adverse Reaction 15](#adverse-reaction)

[14. Pharmacological Class 15](#pharmacological-class)

# Introduction

This document provides technical details on using SPL Release 2 for the
changes in the FDA Requirements on the Content and Format of Labeling
for Human Prescription Drug and Biological Products. The details for
these changes are in the final rule published in the Federal Register,
Volume 71, Number 15, Pages 3922-3997 (January 24, 2006). Among other
things, the rule revises labeling regulations to require inclusion of
Highlights and a table of contents for the Full Prescribing Information
(FPI). In addition, certain labeling sections in the FPI are
reorganized.

This document is a supplement to the *SPL Implementation Guide for FDA
Content of Labeling Submissions -- Release 2a (last updated January 10,
2006),* therefore, the general principles described in the earlier
document remain in effect. The intention is to combine these documents
in the future. The scope in this document is limited to submission of
SPL to FDA. Additional data elements included in SPL release 2 that are
not covered in this document are not part of SPL submitted to FDA at
this time and are outside the scope of this document. Instructions
related to the information to include in Highlights are also outside the
scope of this document. Details on controlled vocabulary referred to in
this document are on the FDA Data Standards Council web site at
<http://www.fda.gov/oc/datacouncil>. References for information on the
content of labeling and examples of SPL XML are also posted on this web
page.

# Stylesheet and Schema

**Information**: The references to the SPL release 2 schema and FDA
stylesheet.

**Terminology**: There is no controlled terminology for this
information.

**SPL location**: This information is in the beginning of the SPL file.

**XML details**: Reference to the stylesheet and schema is provided as
follows:

\<?xml-stylesheet
href=\"http://www.fda.gov/oc/datacouncil/stylesheets/spl/spl.xsl\"
type=\"text/xsl\"?\>

\<document xmlns=\"urn:hl7-org:v3\"
xmlns:xsi=\"http://www.w3.org/2001/XMLSchema-instance\"
xsi:schemaLocation=\"urn:hl7-org:v3
http://www.fda.gov/oc/datacouncil/schemas/spl/spl.xsd\"\>

# FPI Sections and Subsections

**Information**: Sections and subsections have titles and codes.

**Terminology**: LOINC codes are used for sections and subsections.

**SPL location**: The title and LOINC codes are associated with the
section and subsection.

**XML details**: The \<title\> of the sections and subsections and order
of the sections and subsections as they appear in the SPL are used to
render the FPI Contents. Section \<title\> and subsection \<title\> are
bold. The numbering for the sections and subsections are included in the
\<title\> text. Other instructions for "Creating the SPL Body" described
in *SPL Implementation Guide for FDA Content of Labeling Submissions --
Release 2a (last updated January 10, 2006)* are unchanged.

# Recent Major Changes in FPI Text

**Information**: A notation is provided for recent major changes in the
FPI text.

**Terminology**: There is no controlled terminology for this
information.

**SPL location**: The tag is located in the FPI text

**XML details**: The recent major text is tagged using the \<content
styleCode="xmChange"\>. For example:

\<text\>This is an example of text that is not changed.\<content
styleCode="xmChange"\>This is an example of text that is a recent major
change\</content\>This is an example of changed text that is not
considered a recent major change\</text\>

# Adverse Drug Reaction Reporting Information

**Information**: The Highlights includes the company name and contact
information (phone number, web site) for reporting suspected drug
adverse reactions.

**Terminology**: There is no controlled terminology for this
information.

**SPL location**: This information is captured in the SPL general header
elements.

**XML details**: The name of the company is represented in the
\<legalAuthenticator\> child of the \<document\> element. Specific
information regarding the company is included through the immediate
child elements (descendents) of \<legalAuthenticator\> as
\<assignedEntity\> and \<representedOrganization\>. This is illustrated
schematically below:

![](media/image1.png)

The direct \<telecom\> children of the \<assignedEntity\> element are
the contact phone numbers and URL for reporting adverse reactions. Note
that more than one \<telecom\> element is permitted as a child of
\<assignedEntity\> , e.g., a phone number and web site URL as separate
\<telecom\> entities.

The following is representative coding for \<legalAuthenticator\>:

\<document\>

.....

.....

\<legalAuthenticator\>

\<time/\>

\<assignedEntity\>

\<telecom value="tel:place the adverse reaction contact phone number
here"/\>

\<telecom value="http:place the adverse reaction contact web address
here"/\>

\<representedOrganization\>

\<name\>company name here\</name\>

\</representedOrganization\>

\</assignedEntity\>

\</legalAuthenticator\>

\</document\>

Definitions of elements:

1.  \<telecom\> child of \<assignedEntity\>: the \<telecom\> element may
    be used more than once, however, the first instance should provide
    the phone number to be used for reporting adverse reactions.

2.  \<name\> child of \<representedOrganization\>: This should contain
    the name of the organization as it appears in the Highlights.

# Year of Initial US Approval

**Information**: The Highlights provide the 4 digit year (not day or
month) of the initial US approval.

**Terminology**: There is no controlled terminology for this
information.

**SPL location:** This information is captured in the SPL general header
elements.

**XML details**: The 4 digit year of initial US approval as it should
appear in Highlights is contained in the \<time\> child of the
\<verifier\> element. This is illustrated schematically below:

![](media/image2.png){width="2.4916666666666667in"
height="1.492361111111111in"}

For example:

\<verifier\>

\<time value=\"2005\"/\>

\<assignedEntity/\>

\</verifier\>

# Highlights Text

**Information**: The actual Highlights of a rendered SPL is constructed
from three sources: boilerplate text rendered directly from the
stylesheet (e.g., "HIGHLIGHTS OF PRESCRIBING INFORMATION"), data
elements inserted into the boilerplate text (e.g., Initial U.S. Approval
\<year\>), and text blocks corresponding to each major highlights part
(Highlights text). The Highlights text is captured for Boxed Warning,
Recent Major Changes, Indications and Usage, Dosage and Administration,
Dosage Forms and Strengths, Contraindications, Warnings and Precautions,
Adverse Reactions, Drug Interactions, Use in Specific Populations and
Patient Counseling Information.

**Terminology**: There is no controlled terminology for this
information.

**SPL location**: The text blocks for Highlights are coded with the
\<excerpt\> \<highlight\> elements of the major section of labeling in
which they are contained. For example, the Highlights for Indications
and Usage are located with the Indications and Usage section of the
labeling. The Highlights text is placed under the main section and not
under subsections. Note: The first paragraph in the Box Warning
Highlights text is reserved for the "heading" for the concise summary of
the box warning described in the regulations and the second paragraph in
the Box Warning Highlights text is reserved for the statement: "See full
prescribing information for complete boxed warning."

**XML details**: The text blocks of Highlight are coded with the
\<excerpt\> \<highlight\> elements of the section in which they are
contained. The following is sample coding:

[\<component\>]{.mark}

[\<section\>]{.mark}

[\<id root=\"]{.mark}xxxx[\"/\>]{.mark}

[\<code code=\"]{.mark}43685-7[\" codeSystem=\"2.16.840.1.113883.6.1\"
displayName=\"Warnings and Precautions Section\"/\>]{.mark}

[\<title\>5 WARNINGS AND PRECAUTIONS \</title\>]{.mark}

[\<text\>]{.mark}

[\<paragraph\>]{.mark}

[Aplastic anemia has been observed in.....]{.mark}

[\</paragraph\>]{.mark}

[\</text\>]{.mark}

[\<excerpt\>]{.mark}

[\<highlight\>]{.mark}

[\<text\>]{.mark}

[\<list listType=\"unordered\"\>]{.mark}

[\<item\>]{.mark}

> [Aplastic anemia has been observed in 8% of recipients and is
> irreversible in the majority of patients who experience this.
> (\<linkHtml href="#Section_5"\>5\</linkHtml\>)...]{.mark}

[\</item\>]{.mark}

[\<item\>]{.mark}

> [Monitor for hematological adverse reactions every 2 weeks through the
> second month of treatment...]{.mark}

[\</item\>]{.mark}

[ \</list\>]{.mark}

[\</text\>]{.mark}

[....]{.mark}

[\</highlight\>]{.mark}

[\</excerpt\>]{.mark}

[\</section\>]{.mark}

[\</component\>]{.mark}

The following principles are illustrated by this example:

a.  The \<text\> block for the Highlights is included as the \<except\>
    \<highlight\> \<text\> children of the respective section. In the
    example above, the text block rendered in the highlights section is
    the child of the "Warnings and Precautions" section.

b.  The coding of the highlights text block is not in a subsection.

c.  The text block is rendered similar to any other text block, although
    in a location separate from its actual position in the rendered SPL
    document.

d.  Links to the section or subsection where the primary content exists
    are explicitly entered in the Highlights text block.

e.  Section numbering is included in the title of sections and
    subsections (e.g., '5', above).

# Indications

**Information**: For each indication, the code for the intent of use,
indication category and indication are provided.

**Terminology**: The HL7 terminology is used for Intent of Use. The
LOINC code for Medical Problem is used for the indication category
(note: this code is also used as a "Precondition Category"). Medical
conditions are from the VA/KP Problem List subset.

**SPL location**: The data elements are under the Indications and Usage
section of labeling. If there is more than one indication, the data
elements for each indication are under each respective subsection in the
Indications and Usage section for the indication.

**XML details**: The indication is the \<subject\> of the \<excerpt\>
\<highlight\> for the indication section or subsection. A
\<substanceAdminsitration\> is the child of \<subject\>. Coding must
contain the intent of use of treatment (\<reason\>) and the coding of
the specific indication being treated
(\<indicationObservationCriterion\>).

The \<reason\> for treatment is coded via the typeCode attribute of the
reason element, e.g., \<reason typeCode="TREAT"\>. The specific
indication being treated is coded as the \<code\> and \<value\> of the
\<indicationObservationCriterion\>. This is illustrated in the schema
diagrams below:

![](media/image3.png){width="3.109722222222222in"
height="1.6333333333333333in"}

![](media/image4.png){width="3.2104166666666667in"
height="1.0333333333333334in"}

![](media/image5.png){width="3.502083333333333in"
height="1.0166666666666666in"}

The following is sample coding for this section:

\<section\>

\<excerpt\>

\<highlight\>

\<subject\>

\<substanceAdministration\>

\<reason typeCode="xxxx\"\>

\<indicationObservationCriterion\>

> \<code code="44100-6\" codeSystem=\"2.16.840.1.113883.6.1\"
> displayName="Medical Problem\"/\>
>
> \<value xsi:type=\"CE\" code="xxxx\" codeSystem=\"xxxx\"
> displayName="xxxx\"/\>

\</indicationObservationCriterion\>

\</reason\>

\</substanceAdministration\>

\</subject\>

\</highlight\>

\</excerpt\>

\</section\>

Definitions of necessary elements:

1.  \<reason\>: The \<reason\> element contains the typeCode attribute,
    which is the intent of use for the indication.

2.  \<indicationObservationCriterion\>: The
    \<indicationObservationCriterion\> element contains the \<code\> and
    \<value\> children that specify that the indication is for a medical
    problem and the specific indication. The \<code\> element contains
    the code and codeSystem attributes; for the current implementation
    of SPL, the codeSystem is always coded as follows: \<code
    code="44100-6\" codeSystem=\"2.16.840.1.113883.6.1\"
    displayName="Medical Problem\"/\>.

The \<value\> child of \<indicationObservationCriterion\> contains the
code attribute for the actual indication and is coded as \<value
code="xxxx\" codeSystem=\"xxx\" displayName="xxxx\"/\>.

# Maximum Dose

**Information**: The maximum dose is related to a specific amount of
drug over a specific duration of time.

**Terminology**: UCUM is used for the units of both drug amount and
duration of time.

**SPL location**: The maximum dose is coded under the sections or
subsections where it is described. For example, if there is more than
one indication, the maximum dose for each indication is under the
subsection in the Indications and Usage section for the indication.

**XML details**: Maximum dose is specified as the \<maxDoseQuantity\>
element, a child of \<substanceAdministration\>:

\<highlight\>

\<subject\>

\<substanceAdministration\>

\<maxDoseQuantity\>

\<numerator value="xxx\" unit="xxx\"/\>

\<denominator value="xxx\" unit="xxx\"/\>

\</maxDoseQuantity\>

\<reason.....\>

\<precondition...\>

\</substanceAdministration\>

\</subject\>

\</highlight\>

Definitions of necessary elements:

1.  \<maxDoseQuantity\> is coded as 'dose per unit time' of the
    \<numerator\> and \<denominator\> children. For example, "1000 mg
    per 24 hours" would be coded as:

> \<maxDoseQuantity\>
>
> \<numerator value="1000\" unit="mg\"/\>
>
> \<denominator value="24\" unit="h"/\>
>
> \</maxDoseQuantity\>

# Condition of Use

**Information**: There are three types of Condition of Use. One relates
to a use of the drug in a selected subgroup of the larger population
related to a characteristic of the patient such as the patient's age,
race, sex or medical condition. The second relates to the use of the
drug only in conjunction with another drug as an adjunct treatment. The
third relates to the necessity of specific tests for the selection or
monitoring of patients who need the drug.

**Terminology**: The Precondition Categories are LOINC codes. Sex and
race codes are from the NCI Thesaurus. Age is represented by the low and
high value. Age range has both a low and high value. The low value alone
represents "Age greater than or equal to". The high value alone is used
for "Age less than or equal to". Medical conditions are from the VA/KP
Problem List subset. Treatments are from FDA SRS, FDA DRLS, and VA
NDF-RT. Screening and monitoring tests are from LOINC.

**SPL location**: The Conditions of Use are coded under sections or
subsections where they are described. For example, the data elements may
be under the Indications and Usage section of labeling. If there is more
than one indication, the data elements for each indication are under the
subsection in the Indications and Usage section for that specific
indication.

**XML details**: Conditions of Use are represented by the
\<precondition\> and \<protocol\> children of
\<substanceAdministration\>. The \<precondition\> and \<protocol\> are
siblings of \<reason\>.

\<subject\>

\<substanceAdministration\>

\<reason typeCode="xxxx\"\>

\<indicationObservationCriterion\>

....

....

\</indicationObservationCriterion\>

\</reason\>

\<precondition\>

...

\</precondition\>

\<componentOf\>

\<protocol\>

.....

\</protocol\>

\</componentOf\>

\</substanceAdministration\>

\</subject\>

For the purpose of Highlights, children of \<precondition\> include:
\<observationCriterion\>, and \<substanceAdministrationCriterion\>. This
is illustrated schematically below:

![](media/image6.png){width="3.5347222222222223in"
height="1.382638888888889in"}

Definitions of necessary elements:

1.  \<observationCriterion\>:

\<observationCriterion\> is used to code Conditions of Use based on a
characteristic of the patient or a test. For a patient characteristic,
the \<code\> is the Precondition category and the
\<observationCriterion\>\<value\> is the specific characteristic of the
patient. For a test, the \<code\> is the LOINC code for the test. The
\<value\> is for the acceptable test result but at this time the value
is left blank. This is illustrated schematically below:

![](media/image7.png){width="3.1930555555555555in"
height="1.6736111111111112in"}

For example, an indication for a patient age 6 to 12 is coded as
follows:

\<precondition\>

\<observationCriterion\>

\<code code=\"30525-0\" codeSystem=\"2.16.840.1.113883.6.1\"
displayName=\"AGE\"/\>

\<value xsi:type=\"IVL_PQ\"\>

\<low value=\"6\" unit=\"a\"/\>

\<high value=\"12\" unit=\"a\"/\>

\</value\>

\</observationCriterion\>

\</precondition\>

2.  \<substanceAdministrationCriterion\>

![](media/image8.png){width="5.040277777777778in"
height="1.4340277777777777in"}

The \<substanceAdministrationCriterion\> is used for the
co-administration of another agent as a precondition of use for a
specified indication. This element identifies that the coded indication
is for use of the product as an adjunct.

An example of coding a \<substanceAdministrationCriterion\> is
illustrated below:

> \<precondition\>
>
> \<substanceAdministrationCriterion\>
>
> \<consumable\>
>
> \<administrableMaterial\>
>
> \<playingMaterialKind\>
>
> \<code code=\"xxx\" codeSystem=\"xxx\" displayName="xxx\"/\>
>
> \<playingMaterialKind\>
>
> \</administrableMaterial\>
>
> \</consumable\>
>
> \</substanceAdministrationCriterion\>
>
> \</precondition\>

The \<code\> child of \<playingMaterialKind\> i.e., \<code code=\"xxx\"
codeSystem=\"xxx\" displayName="xxx\"/\>, can be an ingredient using the
FDA SRS code system, a drug product using the FDA DRLS code system, or a
pharmacological class using the VA NDF-RT code system.

3.  \<monitoringObservation\>

The \<monitoringObservation\> is used for specific tests for the
selection or monitoring of patients who need the drug.

An example of coding a \<monitoringObservation\> is illustrated below:

[\<componentOf\>]{.mark}

[\<protocol\>]{.mark}

[\<component\>]{.mark}

[\<monitoringObservation\>]{.mark}

[\<code code=\"2160-0\" codeSystem=\"2.16.840.1.113883.6.1\"
displayName=\"serum creatinine\"/\>]{.mark}

[\</monitoringObservation\>]{.mark}

[\</component\>]{.mark}

[\</protocol\>]{.mark}

[\</componentOf\>]{.mark}

If two or more Conditions of Use are stated as disjunction, for example,
the drug is used in patients with Condition of Use x OR Condition of Use
y, the \<substanceAdministration\> has to be repeated for each Condition
of Use.

# Limitation of Use

**Information**: There are a number of reasons to limit the use of the
drug such as contraindications. The Limitations of Use are based on
characteristics of the patient such as the patient's age, race, sex or
medical condition.

**Terminology**: The Limitation of Use/Issues categories are from the
NCI Thesaurus. Precondition Categories are LOINC codes. Sex and race
codes are from the NCI Thesaurus. Medical conditions are from the VA/KP
Problem List subset. Age is represented as a range with a low and high
value. The low value alone represents "Age greater than or equal to".
The high value alone is used for "Age less than or equal to".

**SPL location**: The Limitations of Use are coded under the sections or
subsections where they are described. For example, the data elements may
be under the Indications and Usage section of labeling if this is where
the Limitation of Use is described.

**XML details**: Limitations of Use are coded as \<issue\> within the
indication highlight excerpt. The general structure is shown
schematically as follows:

![](media/image9.png){width="4.561111111111111in" height="3.0625in"}

The following is an example of generic coding of an issue:

\<section\>

\<excerpt\>

\<highlight\>

\<subject\>

\<substanceAdministration\>

\<subjectOf\> \<!\-- Limitation of Use -\>

\<issue\>

\<code code=\"xxx\" codeSystem=\"xxx\" displayName=\"xxxx\"/\>

\<subject\> \<!---Example with an Observation Criterion -\>

\<observationCriterion\>

\<code code=\"xxx\" codeSystem=\"xxx\" displayName=\"xxxx\"/\>

\<value xsi:type=\"CE\" code=\"xxxx\" codeSystem=\"xxx\"
displayName=\"xxxx\"/\>

\</observationCriterion\>

\</subject\>

\</issue\>

\</subjectOf\>

\</substanceAdministration\>

\</subject\>

\</highlight\>

\</excerpt\>

\</section\>

Each \<issue\> 'category is identified by the code attribute of the
\<code\> child element of \<issue\> as in the following example:

\<issue\>

\<code code=\"C50646\" codeSystem=\"2.16.840.1.113883.3.26.1.1\"
displayName=\"CONTRAINDICATION\"/\>

Each Limitation of Use is coded with a new \<issue\>. If a single
Limitation of Use consists of more than one patient characteristic, for
example the drug is contraindicated in patients with both characteristic
x AND characteristic y, the \<subject\> in the \<issue\> is repeated for
each characteristic.

# Drug Interaction

**Information**: Interactions have a contributing factor such as food or
another drug and a consequence such as a medical condition.

**Terminology**: The Limitation of Use/Issue category code for
interaction is used. Contributing factors are from FDA SRS (food or drug
ingredients), FDA DRLS (specific drug products), VA NDF-RT
(pharmacological class), and NCI Thesaurus (general substance such as
"food"). Types of consequences are from the NCI Thesaurus.
Pharmacokinetic effects are from the NCI Thesaurus. Medical conditions
are from the VA/KP Problem List subset.

**SPL location**: The data elements are coded under the section or
subsection where the interaction is described. The same data elements
may be represented in more than one place in the labeling.

**XML details**: Interactions include contributing factors and
consequences.

## Contributing factors

Interactions are coded as \<issue\>s. Each interaction is coded with a
new \<issue\>. Similar to coding of \<issue\>s within indications, these
are coded within the \<excerpt\> \<highlight\> of a section or
subsection. The schematic representation of an issue is reproduced
below:

![](media/image10.png){width="3.4506944444444443in"
height="1.9409722222222223in"}

![](media/image11.png){width="4.595138888888889in"
height="2.6555555555555554in"}

For SPL, the subject of interactions is a \<substanceAdministration\>.

\<excerpt\>

\<highlight\>

\<subject\>

\<substanceAdministration\>

\<subjectOf\>

\<issue\>

\<code code="xxx" codeSystem="xxx" displayName="xxx"/\>

\<subject\>

\<substanceAdministrationCriterion\>

\<consumable\>

\<administrableMaterial\>

\<playingMaterialKind\>

\<code code=\"xxx\" codeSystem=\"xxx\" displayName="xxx\"/\>

\</playingMaterialKind\>

\</administrableMaterial\>

\</consumable\>

\</substanceAdministrationCriterion\>

\</subject\>

\<risk\>

..... \<!---described below

\</risk\>

\</issue\>

\</subjectOf\>

\</substanceAdministration\>

\</subject\>

\</highlight\>

\</excerpt\>

Definitions of necessary elements:

1.  The \<code\> element child of issue contains the Limitation of
    Use/Issue category code for interaction.

2.  The \<code\> element for \<playingMaterialKind\> reflects the
    'contributing factor' for an interaction.

3.  Each interaction is coded in a single \<issue\>. If two or more
    contributing factor together result a consequence, for example, Food
    x AND Food y taken with the Drug causes consequence z, the
    \<subject\> in the \<issue\> is repeated for each contributing
    factor. Similarly, if two or more consequence occur together with an
    interaction, for example, Drug A taken with Drug B causes
    consequence x AND consequence y, the \<risk\> in the \<issue\> is
    repeated for each consequence. Multiple contributing factors and
    multiple consequences in a single interaction are handled the same
    way. On the other hand, if two or more contributing factors can
    independently result in the same consequence, for example Food x OR
    Food y taken with the Drug causes consequence z, there would be one
    \<issue\> for the Food x interaction and another \<issue\> for the
    Food y interaction.

## Consequences

Consequences of an interaction are coded as \<risk\>s, a sibling to the
\<subject\> of an \<issue\>. This includes different types of
consequences such as patient problems or pharmacokinetic effects. These
are coded as \<risk\> \<consequenceObservation\> s:

\<issue\>

\<subject\>

.....

\</subject\>

\<risk\>

\<consequenceObservation\>

\<code code= "xxxx\" codeSystem=\"xxxx\" displayName="xxxx\"/\>

\<value xsi:type=\"CE\" code= "xxxx\" codeSystem=\"xxx\"
displayName="xxxx\"/\>

\</consequenceObservation\>

\</risk\>

\</issue\>

Definitions of necessary elements:

1.  \<code\> \<value\>. The \<code\> \<value\> pair identifies the
    actual outcome of the interaction where the \<code\> is the type of
    consequence and the \<value\> is the consequence.

2.  Each interaction is coded in a single \<issue\>. If two or more
    contributing factor together result a consequence, for example, Food
    x AND Food y taken with the Drug causes consequence z, the
    \<subject\> in the \<issue\> is repeated for each contributing
    factor. Similarly, if two or more consequence occur together with an
    interaction, for example, Drug A taken with Drug B causes
    consequence x AND consequence y, the \<risk\> in the \<issue\> is
    repeated for each consequence. Multiple contributing factors and
    multiple consequences in a single interaction are handled the same
    way. On the other hand, if two or more contributing factors can
    independently result in the same consequence, for example Food x OR
    Food y taken with the Drug causes consequence z, there would be one
    \<issue\> for the Food x interaction and another \<issue\> for the
    Food y interaction..

# Adverse Reaction

**Information**: Adverse Reactions have a medical condition consequence.

**Terminology**: The Limitation of Use/Issue category code for adverse
reaction is used. The only type of consequence is a "Patient problem"
from the NCI Thesaurus. Medical conditions are from the VA/KP Problem
List subset.

**SPL location**: The data elements are coded under the section or
subsection where the adverse reaction is described. The same data
elements may be represented in more than one place in the labeling.

**XML details**: Adverse reactions are coded as described as the
consequence of an interaction. The \<code\> or type of consequence is a
Patient Problem. The \<value\> is the consequence. Each Adverse Reaction
is coded in a single \<issue\>.

# Pharmacological Class

**Information**: Active ingredients and products may be described by
pharmacological class.

**Terminology**: The VA NDF-RT is used for the pharmacological class.

**SPL location**: The pharmacological class for an ingredient is coded
under the drug listing data element for the active ingredient. The
pharmacological class for a product is coded under the Drug Listing data
element for the manufactured medicine.

**XML details**: The pharmacological class of the ingredient is coded
under \<activeIngredient\> and the pharmacological class of a product is
coded under \<manufacturedMedicine\>.

## Active ingredient

The pharmacological class of an active ingredient is the coded as
\<generalizedPharmaceuticalClass\> a child of
\<activeIngredientSubstance\>\<asSpecializedKind\> as described below:

\<manufacturedMedicine\>

\<activeIngredient\>

\<activeIngredientSubstance\>

\<asSpecializedKind\>

\<generalizedPharmaceuticalClass\>

\<code code="xxxx" codeSystem="xxx" displayName="xxx"/\>

\</generalizedPharmaceuticalClass\>

\</asSpecializedKind\>

\</activeIngredientSubstance\>

\</activeIngredient\>

\</manufacturedMedicine\>

Definition of elements

1.  An ingredient may have zero to many pharmacological classes. Each
    one is described with a new \<asSpecializedKind\> element.

## Product

The pharmacological class of the overall \<manufacturedMedicine\> is
coded as \<generalizedPharmaceuticalClass\> , a child of
\<activeIngredientSubstance\>\<specializedKind\> as described below:

\<manufacturedMedicine\>

\<asSpecializedKind\>

\<generalizedPharmaceuticalClass\>

\<code code="xxxx" codeSystem="xxx" displayName="xxx"/\>

\</generalizedPharmaceuticalClass\>

\</asSpecializedKind\>

\</manufacturedMedicine\>

Definition of elements

1.  A product may have zero to many pharmacological classes. Each one is
    described with a new \<asSpecializedKind\> element.