Regulatory Focus™ > News Articles > FDA Aligns With Citizen Petition, Revises Draft Guidance on Pricey Generic Heart Drug

FDA Aligns With Citizen Petition, Revises Draft Guidance on Pricey Generic Heart Drug

Posted 29 August 2017 | By Zachary Brennan 

FDA Aligns With Citizen Petition, Revises Draft Guidance on Pricey Generic Heart Drug

Manufacturers looking to market generic versions of a heart medicine that has been around since the 18th century and seen its price rise by more than 600% in recent years will have to work with a new revised US Food and Drug Administration (FDA) draft guidance released Tuesday.

The revised guidance aligns with a citizen petition filed by Concordia Pharmaceuticals, the manufacturer of the authorized generic version of the drug, known as digoxin (or by the brand name Lanoxin). In that petition filed in December 2015, Concordia contended that FDA "should amend the May 2008 digoxin tablets bioequivalence guidance to reflect digoxin's narrow therapeutic index ('NTI') drug status and recommend more appropriate bioequivalence tests and specifications."

According to FDA, NTI drugs are drugs where "small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity."

Concordia says that four of the five abbreviated new drug applications (ANDAs) for digoxin tablets were approved prior to the issuance of the first digoxin guidance, and all five were approved before the agency's views on NTI drug bioequivalence evolved in conjunction with recommendations by FDA's Advisory Committee for Pharmaceutical Science and Clinical Pharmacology in 2010 and 2011.

"Pursuant to the Agency's contemporary NTI standards, at least some of these drugs would not be bioequivalent to Lanoxin," Concordia says. "Furthermore, ongoing concerns about digoxin bioavailability, content uniformity, dissolution, and potency - as well as recalls due to poor current good manufacturing practices ('cGMPs') and splitting digoxin tablets that may not be bioequivalent to Lanoxin - also raise bioequivalence questions. As a result, these generic digoxin products cannot be therapeutically equivalent to Lanoxin."

FDA Agrees?

According to the revised guidance, FDA concurs at least in part with Concordia's petition and "has concluded that digoxin is a narrow therapeutic index (NTI) drug" based on the following evidence:

  • "The range between digoxin therapeutic and toxic plasma concentrations is narrow;
  • Sub-therapeutic doses or concentrations may lead to therapeutic failure;
  • Digoxin is subject to therapeutic monitoring based on pharmacokinetic measures;
  • Digoxin has small to medium within-subject variability;
  • Doses are adjusted in small increments (less than 20%) in clinical practice."

However, Concordia also recommended in its petition that as a result of the guidance changes, FDA should change the ratings of other approved generic versions of the drug from "AB" to "BX," meaning that FDA would change them from therapeutically equivalent to not therapeutically equivalent.

But according to FDA's Orange Book, the other generics are still listed with an "AB" rating.


The revisions to the draft guidance also come as between 2002 and 2013, the number of manufacturers of digoxin decreased from eight to three after safety-related recalls. During that time, the drug's price also reportedly increased by 637%, according to a perspective from the New England Journal of Medicine. According to the New York Times, only two manufacturers of digoxin remained in late 2013 and prices rapidly increased.

The price and sales of Lanoxin seem to have fluctuated more recently.

According to Concordia's financial statements, the company increased revenues of Lanoxin by more than $8 million in 2016, though "pricing erosion" in the fourth quarter caused revenue to drop. In the first quarter of 2017, Concordia reported a more than $11 million decrease in revenue from Lanoxin, though by the second quarter of 2017, the company says revenue increased by about 9% compared to first quarter, primarily due to higher volumes from Lanoxin and another authorized generic the company sells.

Lanoxin has been marketed in the US since before 1937 but was not approved by FDA until 1997.

Draft Guidance on Digoxin


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