NDA 50797/S-026
`
`
`
`SUPPLEMENT APPROVAL
`
`
`Pfizer, Inc.
`Attention: Sushma Hirani
`Senior Director, Pfizer Global Regulatory Affairs
`235 East 42nd Street (MS 219/9/21)
`New York, NY 10017-5755
`
`
`Dear Ms. Hirani:
`
`Please refer to your supplemental new drug application (sNDA) dated and received July
`09, 2021, and your amendments, submitted under section 505(b) of the Federal Food,
`Drug, and Cosmetic Act (FDCA) for for Zmax (azithromycin extended release) for oral
`suspension, 2 g.
`
`We also refer to our letter dated June 10, 2021, notifying you, under Section 505(o)(4)
`of the FDCA, of new safety information that we believe should be included in the
`labeling for azithromycin products. This information pertains to the risk of cardiovascular
`death.
`
`The agreed upon changes to the language included in our June 10, 2021, letter are as
`follows. New additions are noted by underline and deletion are noted by strikethrough.
`
`Prescribing Information
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`Recent Major Changes
`
`Warnings and Precautions, Cardiovascular Death (5.5) 11/2021
`
`WARNINGS AND PRECAUTIONS
`
`
`
`Cardiovascular Death: Some observational studies have shown an approximately two-
`fold increased short-term potential risk of acute cardiovascular death in adults exposed
`
`Reference ID: 4891810
`
`(b) (4)
`
`

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`NDA 050797/S-026
`Page 2
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`to azithromycin relative to other antibacterial drugs, including amoxicillin. Consider
`balancing this potential risk with treatment benefits when prescribing Zmax. (5.5)
`
`FULL PRESCRIBING INFORMATION-CONTENTS
`
`5.5 Cardiovascular Death
`
`FULL PRESCRIBING INFORMATION
`
`5. WARNINGS AND PRECAUTIONS
`
`5.5 Cardiovascular Death
`
`
`Some observational studies have shown an approximately two-fold increased short-
`term potential risk of acute cardiovascular death in adults exposed to azithromycin
`relative to other antibacterial drugs, including amoxicillin. The five-day cardiovascular
`mortality observed in these studies ranged from 20 to 400 per million azithromycin
`treatment courses. This potential risk was noted to be greater during the first five days
`of azithromycin use and does not appear to be limited to those patients with preexisting
`cardiovascular diseases. The data in these observational studies are insufficient to
`establish or exclude a causal relationship between acute cardiovascular death and
`azithromycin use. Consider balancing this potential risk with treatment benefits when
`prescribing Zmax.
`
` 6
`
` ADVERSE REACTIONS
`
`
`The following clinically significant adverse reactions are described elsewhere in
`labeling:
`
` •
`
` Hypersensitivity [see Warnings and Precautions (5.1)]
`• Hepatotoxicity [see Warnings and Precautions (5.2)]
`• Infantile Hypertrophic Pyloric Stenosis (IHPS) [see Warnings and Precautions (5.3)]
`• QT Prolongation [see Warnings and Precautions (5.4)]
`• Cardiovascular Death [see Warnings and Precautions (5.5)]
`• Clostridioides difficile-Associated Diarrhea (CDAD) [see Warnings and Precautions
`(5.6)]
`• Exacerbation of Myasthenia Gravis [see Warnings and Precautions (5.7)]
`
`
`
`
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4891810
`
`(b) (4)
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`

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`NDA 050797/S-026
`Page 3
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`
`6.2 Postmarketing Experience with Other Azithromycin Products
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`Cardiovascular: Arrhythmias including ventricular tachycardia and hypotension. There
`have been reports of QT prolongation,
`torsades de pointes, and cardiovascular
`death.
`
`Patient Information
`
`What are the possible side effects of ZITHROMAX?
`
`
`Serious heart rhythm changes that can be life-threatening, including heart
`stopping (cardiac arrest), QT prolongation, torsades de pointes, feeling that your
`heart is pounding or racing (palpitations), chest discomfort, or irregular
`heartbeat.
`
`Tell your healthcare provider right away if you or your child feel a fast or irregular
`heartbeat, get dizzy or faint.
`
`Other labeling changes unrelated to the FDAAA SLC
`
`ADVERSE REACTION (6) section , Postmarketing Experience with Other
`Azithromycin Products (6.2) subsection was revised to harmonize the prescribing
`information (PI) with other azithromycin lableing
`
`PATIENT COUNSELING INFORMATION (17) and Patient Information was revised to
`substitute the word “doctor “ with the “healthcare provider”.
`
`Patient Information section was revised to add the following to harmonize the Patient
`Information with other azithromycin labeling .
`
`Zmax may cause a rare heart problem known as prolongation of the QT interval. This
`condition can cause an abnormal heartbeat and can be very dangerous. The chances of
`this happening are higher in people:
`o who are elderly
`o with a family history of prolonged QT interval
`o with low blood potassium
`o who take certain medicines to control heart rhythm (antiarrhythmics)
`
`In addition, Clostridium difficile was replaced with Clostridioides difficile in the
`PI. Minor editorial revisions were also made throughout the PI.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4891810
`
`(b) (4)
`
`(b) (4)
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`

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`NDA 050797/S-026
`Page 4
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`
`APPROVAL & LABELING
`
`We have completed our review of this application, as amended. It is approved, effective
`on the date of this letter, for use as recommended in the enclosed agreed-upon
`labeling.
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the
`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using
`the FDA automated drug registration and listing system (eLIST), as described at
`FDA.gov.1 Content of labeling must be identical to the enclosed labeling (text for the
`Prescribing Information, Patient Package Insert), with the addition of any labeling
`changes in pending “Changes Being Effected” (CBE) supplements, as well as annual
`reportable changes not included in the enclosed labeling.
`Information on submitting SPL files using eList may be found in the guidance for
`industry SPL Standard for Content of Labeling Technical Qs and As.2
`
`The SPL will be accessible from publicly available labeling repositories.
`
`Also within 14 days, amend all pending supplemental applications that include labeling
`changes for this NDA, including CBE supplements for which FDA has not yet issued an
`action letter, with the content of labeling [21 CFR 314.50(l)(1)(i)] in Microsoft Word
`format, that includes the changes approved in this supplemental application, as well as
`annual reportable changes. To facilitate review of your submission(s), provide a
`highlighted or marked-up copy that shows all changes, as well as a clean Microsoft
`Word version. The marked-up copy should provide appropriate annotations, including
`supplement number(s) and annual report date(s).
`
`REPORTING REQUIREMENTS
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`
`
`
`
`
`1 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
`2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
`Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4891810
`
`

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`NDA 050797/S-026
`Page 5
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`If you have any questions, call Jacquelyn Rosenberger, PharmD, RAC, Regulatory
`Project Manager, at (301) 796-9179.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Dmitri Iarikov, MD, PhD
`Deputy Director
`Division of Anti-Infectives
`Office of Infectious Diseases
`Center for Drug Evaluation and Research
`
`ENCLOSURE(S):
`• Content of Labeling
`o Prescribing Information
`o Patient Package Insert
`
`
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4891810
`
`

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`Signature Page 1 of 1
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`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
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`/s/
`------------------------------------------------------------
`
`DMITRI IARIKOV
`11/22/2021 09:26:47 AM
`
`Reference ID: 4891810
`
`(
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