Fuhgeddaboudit: FDA Takes a Different Road on Generic PRECEDEX and Issues Letter Decision Allowing ANDA Labeling Carve-Outs

August 18, 2014

By Kurt R. Karst –       

We were beginning to wonder whether FDA would ever issue a letter decision addressing the novel issues raised in the Agency’s January 15, 2014 “Dear NDA/ANDA Applicant” letter (Docket No. FDA-2014-N-0087) concerning approval of generic versions of Hospira, Inc.’s (“Hospira’s”) PRECEDEX (dexmedetomidine HCl) Injection, 100 mcg (base)/mL packaged in 200 mcg(base)/2 mL single-dose vials.  The days turned into weeks, and the weeks into months.  But earlier today, FDA finally issued the highly anticipated decision. [UPDATESubsequent to posting we learned of a lawsuit filed early on August 19, 2014 challenging the FDA Letter Descision.  Links to the papers in that case are provided below.]  And the decision was probably surprising to many.  Instead of addressing head-on the novel generic drug labeling “carve-in” and patent use code issues FDA initially raised in the Agency’s “Dear NDA/ANDA Applicant” letter – and that were the subject of numerous comments – FDA instead ruled that generic dexmedetomidine is a straight-on labeling carve-out case, similar to that faced by the Agency when it initially considered approving generic versions of PRANDIN (repaglinide) Tablets (prior to the change in patent use code issue that was ultimately ruled on by the U.S. Supreme Court in Caraco Pharmaceutical Laboratories, Ltd. v. Novo Nordisk A/S, 132 S. Ct. 1670 (2012)).  That treatment of the case is immediately apparent in the second paragraph of FDA’s August 18, 2014 Letter Decision:

Today’s letter reflects FDA’s determinations with respect to permissibility of labeling carve outs for ANDAs referencing Precedex.  For the reasons set forth below, FDA concludes that regardless of whether the original use code or the revised use code applies, the agency can approve an ANDA that submits a “section viii” statement and omits labeling that discloses the protected use (as identified by Hospira).  FDA further concludes that such omissions do not render the drug less safe or effective for the remaining non-protected conditions of use.

For much of the backgound on this case, we refer you to our previous post; however, here are a few key facts to keep in mind:

  • PRECEDEX is currently approved in three strengths and for two indications: (1) sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting; and (2) sedation of non-intubated patients prior to and/or during surgical and other procedures. 
  • FDA’s Orange Book currently lists one unexpired patent for the 100 mcg (base)/mL packaged in 200 mcg(base)/2 mL single-dose vials strength at issue: U.S. Patent No. 6,716,867 (“the ‘867 patent”), which expires on March 31, 2019, but is subject to a period of pediatric exclusivity that expires on October 1, 2019. 
  • The ‘867 patent is listed in the Orange Book as a method-of-use patent with a “U-1472” patent use code, which is defined in an Orange Book addendum as: “INTENSIVE CARE UNIT SEDATION, INCLUDING SEDATION OF NON-INTUBATED PATIENTS PRIOR TO AND/OR DURING SURGICAL AND OTHER PROCEDURES.”
  • The ‘867 patent was previously listed with a “U-572” patent use code defined as “INTENSIVE CARE UNIT SEDATION.”

The general question FDA initially had to address was whether FDA could, in light of the the original and clarified patent use code narratives, approve an ANDA for a generic version of PRECEDEX containing a “section viii” statement to omit information protected by the ‘867 patent, or whether the omission of such information would preclude a carve-out and ANDA approval.  Or, as FDA explains it in the Agency’s Letter Decision:

Hospira asserts that both its original and its revised use code overlap not only with the first indication for Precedex but also with the second indication for that drug because there is a subset of non-intubated patients that may receive Precedex for procedural sedation (the second indication) in the ICU setting.  Hospira argues that because its use code(s) for the ‘867 patent fully cover the first indication and may overlap with the second indication, an applicant with a section viii statement to the ‘867 patent must carve out both the first and the second indications in their entirety, thereby precluding approval of any ANDAs with carved out labeling.

Among other things, Hospira cited the Caraco decision in which the Court stated: “the FDA will not approve an ANDA if the generic’s proposed carve out label overlaps at all with the brand’s use code.”

After affirming FDA’s authority to determine permissible labeling carve-outs, the Agency, pointing to precedent labeling carve-out decisions involving generic repaglinide (Docket Nos. FDA-2008-P-0343 & FDA-2008-P-0411), tramadol HCl (FDA Docket Nos. 2001P-0495, 2002P-0191, FDA-2002-P-0003), and oxandrolone (Docket No. FDA-2005-P-0368) rejected Hospira’s arguments.  According to FDA:

Both the original and the revised use codes are limited to “intensive care unit sedation.”  Although the revised use code includes additional language specifying some of the types of patients that Hospira claims are encompassed within the “intensive care unit sedation” use, i.e., non-intubated ICU patients prior to and/or during surgical and other procedures, it does not broaden the claimed method of use beyond “intensive care unit sedation.” . . .  Nor does the clarified use code and its explicit inclusion of a subset of patients that may undergo procedural sedation somehow expand the patented use to encompass and prevent approval for all patients who seek to use the drug for the separately delineated procedural sedation indication. . . .  FDA previously has determined that it can approve ANDAs for broad, general indications that may partially overlap with a protected method of use, so long as any express references to the protected use are omitted from the labeling.  The procedural indication and related information in the labeling do not impermissibly disclose the use of Precedex for procedures in the ICU (i.e., for the use covered by the use code).  ANDAs therefore may be approved for the second indication, consistent with how FDA has implemented use codes and allowed carve outs in other circumstances.


Just as FDA concluded that a labeling carve out was proper for repaglinide before Novo broadened its use code to duplicate in its entirety the single approved indication, so, too, here ANDAs for Precedex may carve out the protected information (related to use for ICU sedation), and be approved for procedural sedation despite the fact that use for procedural sedation may at times occur in an intensive care setting.  Use in an intensive care setting is not expressly disclosed in any proposed ANDA labeling.  Hospira’s reliance on a single sentence about a different type of “overlap” at issue in Caraco does not control the outcome here.

From there it was relatively easy for FDA to conclude that “permitting ANDA sponsors to omit information from the labeling related to use for ICU sedation does not render the product less safe or effective for the remaining use of sedation of non-intubated patients prior to and/or during surgical and other procedures,” which is a finding that must be made in labeling carve-out cases pursuant to 21 C.F.R. § 314.127(a)(7).

Whether FDA’s side-stepping of several of the issues the Agency initially raised last January was a deliberate attempt to avoid having to address those thorny issues, or the result of an epiphany that this is, to the Agency at least, a “straight 8 case” is unclear.  Certainly one thing was clear all along: at least one party involved in the dispute would be disappointed with FDA’s result.  Now the question is: how disappointed?


  • Early on August 19, 2014, Hospira filed a Complaint and Motion for Temporary Restraining Order and/or Preliminary Injunction in the U.S. District Court for the District of Maryland to stay FDA's Letter Decision, rescind any ANDA approvals predicated upon that Letter Decision, order FDA to recall any product sold or distributed under such an ANDA approval, and enjoin FDA from granting any further or additional approvals predicated upon the Letter Decision.
  • PAPERLESS ORDER (Entered: 08/19/2014)) scheduling an emergency hearing on the Motion for Temporary Restraining Order for Tuesday, August 19, 2014 at 3pm in Courtroom 2C. 
  • ORDER directing that the decision of Defendant Food and Drug Administration (FDA), in Docket No. FDA-2014-N-0087 is STAYED; directing that this order is to remain in effect until September 2, 2014.  Temporary Restraining Order Granted.