Labeling Review Memo, September 12, 2013 - RAGWITEK

MEMORANDUM
Department of Health and Human Services
Public Health Service
Food and Drug Administration
Center for Biologics Evaluation and Research

______________________________________________________________________

Date: September 12, 2013

From: Kristine T. Khuc, Pharm.D.
 Consumer Safety Officer
 Advertising and Promotional Labeling Branch (APLB) (HFM-602)
 Division of Case Management

Through: Lisa L. Stockbridge, Ph.D.
 Branch Chief
 Advertising and Promotional Labeling Branch (APLB) (HFM-602)
 Division of Case Management

To: Katie Rivers, M.S., RPM, CBER/OVRR/DVRPA
 LCDR Elizabeth Valenti, M.P.H., R.A.C., Chairperson, CBER/OVRR/DBPAP/LIB
 Ronald Rabin, M.D., Clinical Reviewer, CBER/OVRR/DBPAP/LIB

Subject: Labeling Review
RAGWITEK (Short Ragweed Pollen Allergen Extract)
BLA: 125478/0
 Sponsor: Merck Sharp & Dohme Corp.
 ______________________________________________________________________

Background: The sponsor submitted: 
X New Approval
 Changes Being Effected (CBE) supplement 
____ Prior Approval Supplement (PAS) Amendment
 Major Amendment

Submission contains:

X Prescribing Information (PI)
X Patient Package Insert (PPI)
X Carton and/or container labels
 Other

APLB Comments/Recommendations

This labeling review is for an original Biologics License Application (BLA) submitted on March 11, 2013 by Merck, for RAGWITEK (Short Ragweed Pollen Allergen Extract). The action due date is March 11, 2014. Upon reviewing the submission, APLB has the following comments from a promotional and comprehension perspective.

General 
•Use active voice and command language wherever possible.
•Upon approval, please revise “-----b(4)----------------” with the proprietary name.

Highlights 
•The product title consists of the proper name, including any appropriate descriptors, followed (on a separate line) by the product’s dosage form and route of administration. For example:

RAGWITEK® (Standardized Allergenic Extract, Short Ragweed (Ambrosia artemislifolia) 
Tablet for sublingual use
•In ADVERSE REACTIONS, the second bullet minimizes the fact that the systemic reactions occurred with Ragwitek. Thus, we suggest revising this bullet to the following:

Ragwitek may cause systemic allergic reactions. Signs and symptoms of a systemic reaction include: nausea, lightheadedness, edema of the mouth and throat, throat tightness, dysphagia, and dyspnea.
•Because the full prescribing information states that Ragwitek treatment should not be initiated in a pregnant woman, this information should be included in the USE IN SPECIFIC POPULATIONS section.
•Once approved, include the year in the Initial U.S. Approval section.

DOSAGE AND ADMINISTRATION

Place the bolded statement “For sublingual administration only.” beneath the heading DOSAGE AND ADMINISTRATION.

DOSAGE FORMS AND STRENGTHS

Revise the dosage form to tablet.

Contraindications 
•Asthma has not been contraindicated in the other draft labels for allergenic extracts. Is this truly a contraindication for RAGWITEK?
•Please list the contraindications as described in the Draft Guidance for Industry: Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human Prescription Drug and Biological Products – Content and Format. We suggest listing out the excipient ingredients.

Warnings and precautions
 Please revise this section by combining the third bullet with the first bullet. The last bullet contains information on educating patients on the signs of symptoms of a severe allergic reaction and
 belongs in section 17 PATIENT COUNSELING INFORMATION.

ADVERSE REACTIONS

In the first bullet, delete the phrase, “and more commonly than placebo.”

FULL PRESCRIBING INFORMATION: CONTENTS 
•Please revise the CONTENTS to be consistent with the revisions of the FULL PRESCRIBING INFORMATION.

Full Prescribing Information 
2 Dosage and Administration 
•Directly beneath this section, include the directive (in bold):

For sublinqual administration only.
•Revise this section by using active voice and command language.
•We recommend combining the first two subsections. Thus, revise subsection 2.1 to the header “Dose” and subsection 2.2 as “Administration.”

3 dosage forms and strengths

Delete information relating to the tablet color and engraving from this section as this information belongs in section 16 HOW SUPPLIED/STORAGE AND HANDLING. 

4 CONTRAINDICATIONS

List the excipient ingredients that are contraindicated in patients who may have a hypersensitivity. (See Draft Guidance for Industry: Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human Prescription Drug and Biological Products – Content and Format) 

5 Warnings and Precautions 
•Revise this section using active voice and command language, as appropriate.
•Consider revising the section title for 5.1 to Hypersensitvity Reactions. Create separate paragraphs for local and systemic allergic reactions.

Under subsection 5.1, delete the first phrase “As with any allergen immunotherapy...” because it minimizes the risk associated with RAGWITEK.

 Avoid redundancy. Delete the description of the signs and symptoms associated with a systemic allergic reaction as this description is also stated in section 6 ADVERSE REACTIONS.

The last sentence in this subsection regarding patient education belongs in section 17 Patient Counseling Information.
•Describe the actual risk associated with asthmatic patients. For example:

Uncontrolled asthmatic patients may be at a higher risk because of a decreased ability to survive a systemic allergic reaction.
•For subsection 5.4, be informative and specific with title headings. Consider creating multiple subsections to further separate and define each risk.

Delete the first sentence underneath the subsection title regarding epinephrine. Information under this subsection about its lack of use in this population may suggest off-label use.

Refrain from using vague phrases such as, “use with caution.”

In the last sentence of this subsection, delete the phrase, “As with other immunotherapy.” Consider moving the sentence “Patients may have local swelling which is severe or increases in severity over time…” to subsection 5.1 Hypersensitivity Reactions.

6 Adverse Reactions
•Move and place the list of the most common adverse reactions with the cut-off frequency directly beneath the heading Adverse Reactions.
•Purse the second paragraph as stated above.
•Be consistent in naming “studies” as “trials” in subsection 6.1.
•Add a description of the most serious adverse reactions.
•Avoid using vague phrases, such as “mild and transient” and “recurrent symptoms generally resolved over time.” Delete or clearly define and provide data for the terminology.
•Delete the phrase, “and more commonly than placebo.”
•Revise the title for Table 1 as:

Adverse Reactions Reported in =1% of Adult Patients with Grass Pollen Induced Rhinoconjunctivitis with or without Asthma Treated with RAGWITEK.

7 DRUG INTERACTIONS

Delete this section if there are no data to report.

8 USE IN SPECIFIC POPULATIONS
•Delete the second sentence under subsection 8.1 Pregnancy. This sentence provides information on another sublingual allergenic extract, not information specific to RAGWITEK.
•Delete the last sentence of subsection 8.5 Geriatric Use. Information in this PI should contain data and clinical experience specific to RAGWITEK.

11 DESCRIPTION
•Include the pharmacologic class of the product.
•Provide a detailed description of the physical and chemical properties of the drug.

12 CLINICAL PHARMAOCOLOGY

Delete subsection 12.3 if there is no data to report.

14 Clinical Studies
•Delete the period after the section number in the section header.
•Delete any subsections here. There is no subsection 14.1.
•Be consistent in naming “trials” as “studies” in this section.
•Avoid using the term “significant relief.” This term is promotional in tone in the absence of clarifying the term with statistical data. Likewise, provide clarification and qualify the terms “improved” “improvement” and “significant improvement.”

16 HOW SUPPLIED/STORAGE AND HANDLING
•It is not necessary to subsection this section. The use of a subsection is cumbersome and decreases readability in this case.
•Add in information regarding expiry date.

17 Patient Counseling Information 
•Revise this section by using active voice and command language.
•To enhance readability, format this section using bullets. Do not bold the subheadings.
•For the subsection on Systemic Allergic Reactions, combine related information into one paragraph, for example, move information in the third paragraph to the first paragraph.

LOGO

Remove the logo at the end of the PI.

VERSION DATE

Do not place the version date at the end of the PI. This information is captured in the HIGHLIGHTS.

PATIENT INFORMATION LEAFLET

Under “Are there any reasons to stop taking RAGWITEK?,” please revise the directive to:

Know the medicines you or your child take. Keep a list of them and show it to your doctor and pharmacist each time you get a new refill of RAGWITEK.

CARTON AND CONTAINER LABELS

We have no objections to the proposed principal display panels at this time.

The above comments have been provided to OVRR as a labeling consult. If you have any questions regarding this review please contact Kristine T. Khuc, Consumer Safety Officer, at 301-827-6332.
