l 

~"'~4~ ...,o,,.,~. DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service f- Food and Drug Administration 

~ Center for Drug EYaluation and Research ....,.,....." ---- - --- ------------------- - --- """"--------------­

CERTIFIED MAIL-RETURN RECEIPT REQUESTED 

Par Pharmaceutical 4 / 19/ 2016 

Attention: Anh Tran-Cao 

Senior Director, Regulatory Affairs 

9601 Jeronimo Road 

Irvine, CA 92618 

Dear Madam: 

This letter is being sent under Section 506C{f) of the Federal Food, Drug, and 

Cosmetic Act {FD&C Act) for the reasons set forth below. 

Section 506C of the FD&C Act requires a manufacturer of a drug product that is 

" life -supporting, life-sustaining, or intended for use in the prevention or 

treatment of a debilita ting disease or condition" to notify the Food and Drug 

Administration {FDA or the Agency) of: {1) a permanent discontinuance in the 

manufacture of the drug; or {2) an interruption of the manufacture of the drug that 

is likely to lead to a meaningful disruption1 in the supply of that drug in the 

United States; and {3 ) the reason(s) for such discontinuance or interruption of 

manufacturing (FD&C Act§ 506C(a)) . The notification must be submitted at least 6 

months prior to the date of the discontinuance or interruption of manufacturing, or 

as soon as practicable (FD&C Act§ 506C{b)). Compliance with t his notification 

requirement is essential to facilitating the mitigation and/ or prevention of a 

shortage or potential shortage, and ultimately may ensure availability of critical 

drugs for patients. 

If a person fails to submit this required notification within the required 

timeframe, FDA must issue a letter to that person informing the person of the 

failure to comp ly with the FD&C Act (FD&C Act§ 506C{f)). 

Tretinoin capsules are a product that is " life-supporting, life-sustaining, or 

intended for u s e in the prevention or treatment of a debilitating disease or 

condition." This product has an approved indication for the i nduction of r emission 

in patients with acute promyelocytic leukemia (APL) , French-American-British (FAB) 

classification M3 (including the M3 variant), c haracterized by the presence of the 

t(l5;17) translocation and/or the presence of the PML/RARa gene who are refractory 

to, or who have relapsed from, anthracycline chemotherapy, or for whom 

anthracycline-based chemotherapy is contraindic ated. It is our understanding that 

sometime during November 2015, there was an interruption in the manufacture of 

tretinoin capsules. This interruption was likely to lead to a meaningful 

disruption in the suppl y of this drug product in the Unite d States. The Agency 

learned o f the disruption from outside stakeholders in February 2016, and tretino in 

capsules were determined to be in shortage soon thereafter, on February 19, 2016. 

Our records indicate that Par Pharmac eutical did not notify FDA of the interruption 

in manufacture of this product. Accordingly, we are issuing you this letter to 

notify you of your noncompliance with the FD&C Act. 

1 The statute defines "meaningful disrupti on" to mean " a change in producti on that 

is reasonably likely to lead to a reduction in the supply of a drug by a 

manufacturer that is more than negligible and affects the ability of the 

manufacturer to fill orders or meet expected demand for the product ," and "does not 

include interruptions in ma nufacturing due to matters such as routine maintenance 

or insignificant c hanges in manufacturing so long as the manufacturer expects to 

resume operations in a short period of time ." Section 506C(h) (3). 
No later than thirty calendar days after the issuance of this letter, you must 

submit to the Agency a written response setting forth the basis for noncompliance 

with Section 506C and prov iding the required notification, including the reason(s) 

for the interruption in manufacturing that led to a disruption in the supply of 

tretinoin capsules in February 2016 . 

No later than forty-five calendar days a fter the issuance of this letter, FDA will 

make this letter and your response to the letter available to the public on FDA' s 

Drug Shortage website, unless the Agency determines that this letter was issued in 

error, or, after review o f your response, determines that there was a reasonable 

basis for noncompliance . In posting the letter and your response on the Drug 

Shortage website, FDA would protect confidential commercial information and trade 

secrets, if arty, as required by applicable l aw. 

If you have further questions, please contact the Drug Shortage Staff at (301) 796­

1300. 

Please submit all communi cations regarding this drug product to the following 

address: 

Drug Shortage Staff 


Food a nd Drug Administration 


WO 22, Room 6204 


10903 New Hampshire Avenue 


Silver Spring, MD 20993 


Sincerely, 

CAPT Valerie Jense n 

Associate Director 

Drug Short age Staff 

Center for Drug Evaluation and Research