In August 2025, NRx Pharmaceuticals asked FDA to remove from the market nearly every injectable ketamine product sold in the United States, on the ground that they contain the preservative benzethonium chloride. Fourteen months later the agency has not decided. The 37-page toxicology report the petition rests on makes one central regulatory claim, that FDA has never evaluated the preservative for intravenous use, and that claim is contradicted by FDA’s own published dataset. The report also gives its key exposure figure twice, in two places, and the two masses differ by exactly a factor of ten.
On October 30 the same company announced something else: that FDA had approved its own abbreviated application for a preservative-free injectable ketamine, made for it by Nephron Pharmaceuticals in South Carolina. That approval is reported from the company’s release. It had not appeared in the four FDA sources checked on October 31, which is consistent with the lag in those datasets and is not evidence against it, and it does not touch the petition. Nothing in it indicates FDA accepted any argument the petition makes.
The two matters together are what make the evidence worth reading closely. The petitioner now has an approved product in the category it is asking the agency to clear.
What the petition asks, and what its report concludes
The report was prepared for the company by a Tampa regulatory consultancy and is dated July 21, 2025, five weeks before the petition was filed.
Its own account of what it supports is narrower than the petition built on it. The executive summary says the assessment “supports a Citizen Petition under 21 CFR §10.30 requesting the reformulation, relabeling, or market withdrawal” of the affected products. Reformulation and relabeling are not a ban. The report closes by saying that continued use in parenteral formulations “may warrant regulatory reevaluation.”
The petition asks for removal from the market.
The database claim
The report’s central regulatory argument is that the preservative has never been evaluated for the route in question. Its executive summary states that benzethonium chloride “is not designated as Generally Recognized as Safe (GRAS) for parenteral use and is not listed for intravenous administration in the FDA Inactive Ingredient Database.” A later section repeats it: the preservative “is not listed in the FDA’s Inactive Ingredient Database (IID) for use in parenteral drug products, including intravenous formulations.”
That is not what the database says. FDA publishes the inactive ingredient database as a downloadable dataset. In the January 2024 edition, eighteen months before the report was written, benzethonium chloride appears six times, including two entries directly on point:
- intravenous, injection, maximum daily exposure 1 mg
- intramuscular, injection, maximum daily exposure 1 mg
A third covers intravenous injectable powders at a maximum potency of 0.5 mg per unit dose. The same entries appear in the edition PH Health printed and attached to its opposition in September 2025, and in the current edition. The listing was there before the report was written, and it is there now.
The distinction matters in both directions, and neither party states it carefully. A listing is not a finding that any proposed exposure is safe. It records the highest level at which FDA has already approved an ingredient for a given route, which is why applicants can reference it instead of generating fresh excipient safety data. So the report is wrong that the ingredient is absent, and PH Health reaches too far when it treats the listing as evidence that the preservative is “generally recognized as safe for use in injection products.”
What the database supplies is more useful than either characterization: a number.
The arithmetic
The report models a worst case. In critical care, it says, maintenance infusions may run at 2 mg/kg/hour for up to 24 hours. For a 60 kg adult that is 2,880 mg of ketamine in a day. Ketalar’s lowest strength carries 0.1 mg of preservative per mL in a 10 mg/mL solution, a ratio of 0.01 mg of preservative per mg of ketamine. The report multiplies it out on page 9: 28.8 mg, which distributed instantly into five liters of blood would give roughly 12.86 µM, a concentration the report says “substantially exceed[s]” the 2.5 µM at which benzethonium has been shown in vitro to trigger eryptosis, the programmed death of red blood cells.
On page 27 the report runs the same scenario again. Same adult, same rate, same duration, same 2,880 mg of ketamine, same five liters of blood. This time the answer is 2.88 mg and roughly 1.15 µM, a concentration the report describes as approaching, not exceeding, the same threshold. The executive summary uses the lower figure. So does the risk-benefit section.
The two masses differ by exactly a factor of ten, and they are not two scenarios. Under the ratio the report itself states, 28.8 mg is the arithmetically correct result and 2.88 mg is an error.
The printed concentrations do not line up either, and the gap between them is not the same gap. The report converts on a molecular weight of 448 g/mol, which turns 28.8 mg in five liters into 12.86 µM. The same conversion applied to 2.88 mg gives about 1.29 µM, not the 1.15 µM the page prints. So the lower passage carries two separate defects: a tenfold error in the mass, and a further conversion error in the concentration derived from it, which is why the printed concentrations differ by about 11.2-fold rather than ten. The sections most likely to be read carry the lower figure, and it is the one that understates the exposure. PH Health told FDA that the report gives 28.8 mg in one place and 2.88 mg in another, without saying which is right.
PH Health’s lawyers ran the calculation a third way. Ketalar’s label caps maintenance infusion at 0.5 mg per minute, a quarter of the rate the report models, and the highest strength contains a tenth as much preservative per mg of ketamine as the lowest. Hold to the label on both and a 24-hour infusion delivers about 0.72 mg. The 40-fold gap between that and 28.8 mg is exactly the product of the two departures: four times the infusion rate multiplied by ten times the preservative ratio.
Now set those numbers against the 1 mg daily ceiling in the database the report said did not list the ingredient. Labeled use falls below it. The report’s modeled scenario exceeds it, whichever of its two figures is used. A 10 mL vial of Ketalar carries 1 mg of the preservative, the same number.
That is the dispute, stated precisely. It is not about whether benzethonium is biologically active, which the published literature supports and PH Health does not seriously contest. It is about whether an infusion rate four times the label should drive a label-wide withdrawal.
What the October 30 release repeats
The announcement restates the petition’s case. Three of its claims sit awkwardly against the record.
| The release says | What the record shows |
|---|---|
| Patients dosed “for labeled indications” may exceed FDA’s 1 mg maximum daily exposure | The exposure comes from a 2 mg/kg/hour infusion, which Ketalar’s label does not authorize. Under the labeled maximum the figure is about 0.72 mg. The report calls its own estimate a theoretical upper bound |
| The preservative is “banned from new drugs, consumer hand cleansers, wipes, healthcare or surgical hand rubs” | FDA’s 2019 final rule on consumer antiseptic rubs found it ineligible for the OTC monograph, so such products need an approved application before marketing. That is a change of pathway, not a ban from new drugs, and it does not concern an inactive ingredient in an injectable |
| Ketamine injection “has been in short supply since 2018 and currently appears on the FDA drug shortage list” | FDA’s shortage database distinguishes current shortage, to be discontinued, and resolved. Searched October 31, it returns one ketamine entry, status “To Be Discontinued,” posted November 7, 2025. Ketamine is on the list. It is not listed as in shortage |
Where each side overreaches
The report calls its 2 mg/kg/hour scenario “FDA-approved ketamine dosing.” It is not. But the report does cite real evidence that the practice occurs, including a 2024 prospective cohort of prolonged ketamine infusions in a pediatric intensive care unit at 1 to 2 mg/kg/hour for a median of five days. PH Health’s response, that the modeling “grossly mischaracterize[s] exposure” under labeled conditions, is accurate about the label and silent about the intensive care literature.
The report is candid where it matters least and assertive where it matters most. It concedes its estimate is “a theoretical upper bound” that ignores protein binding, renal clearance and tissue sequestration. It also asserts, without support, that “in the current health care delivery environment, multi-dose vials have no practical application.”
PH Health has its own weak point, and it is the argument it presses hardest. Having told FDA that the preservative may be pharmacologically active enough to change how a product behaves, it argues that any preservative-free generic referencing Ketalar must therefore produce in vivo bioequivalence data rather than receive a waiver. The regulation supports the mechanism: under 21 CFR 320.22, a parenteral solution’s bioequivalence is self-evident only if it contains “the same active and inactive ingredients in the same concentration” as the reference product. Remove the preservative and that route closes. But this is a party’s litigation position, not an FDA finding, and the agency has now approved preservative-free ketamine twice.
The preservative-free product already approved
On September 17, 2025, nine days before PH Health told FDA that “there is currently no FDA-approved injectable ketamine formulation that does not use BZT,” FDA approved one. Baxter’s ANDA 219684 covers a single-dose prefilled syringe whose label lists no preservative, only ketamine and sodium chloride in water. NRx’s October 30 release makes the mirror-image claim, that “currently all available ketamine injection products contain benzethonium chloride.”
The approval contradicts PH Health outright. It qualifies NRx’s claim without refuting it, because that claim is about what is available, and availability is the part the records do not establish: the federal databases still disagree with each other about which Baxter presentation is marketed. Neither presentation carries a therapeutic-equivalence rating, so neither can be substituted at the pharmacy counter for Ketalar the way the AP-rated generics can, and both are the lowest concentration, 10 mg/mL, so neither replaces the 50 and 100 mg/mL vials anesthesia runs on.
Approval, listing, marketing, distribution and reliable supply are five different things. For Baxter the first two are established and the rest are not visible in the public record. For NRx, by its own account, only the first has happened. And FDA’s shortage database holds no current ketamine shortage for a withdrawal to worsen, so no public data would let anyone quantify what one would do to clinic supply.
What the approval changes
When the petition was filed, NRx had no approved product in the category it was asking FDA to clear. By its own account it now does.
The company’s own quarterly report puts the two things in consecutive sentences: NRx “has additionally submitted a citizen petition seeking to have benzethonium chloride, a toxic preservative, removed from all commercial presentations of ketamine,” and “management believes that the current generic market for ketamine exceeds $750 million per year.” The same filing names the generic among its lead candidates alongside an intravenous formulation still in the NDA process, and the toxicology report leans on that second candidate, citing preservative-free formulations “currently under FDA review” as evidence that parenteral ketamine can be made without the preservative.
With an approval in hand, the petition now carries a concrete competitive consequence it did not carry before. If FDA were to grant it, or to require reformulation or withdrawal by any other route, the products removed would be the AP-rated generics that hold the substitutable positions, and the approved preservative-free products would be the ones left. Whether that happens is entirely undecided: the docket’s only substantive entry remains the interim response of March 4, 2026, the standard letter the agency sends when it cannot meet the 180-day deadline, saying the petition “raises complex issues requiring extensive review and analysis.”
PH Health’s interest runs the other way: it holds the Ketalar approval the petition would withdraw. Disclosing an incentive is not misconduct, and the existence of one on either side says nothing about whether the preservative is safe.
The evidentiary question stands on its own. On the record FDA has in front of it, the petition asks for more than its own science supports. A report whose own conclusion is that the preservative “may warrant regulatory reevaluation” has become the basis for a request to withdraw the category; the commercial consequence of that request is now documented in the petitioner’s own filings, and what the company intended by it is not something the docket establishes. The report’s strongest factual claim, about the agency’s own database, is wrong and was checkable on the day it was written. The exposure figure its summary relies on is the one its own ratio contradicts by a factor of ten.
Neither side has put patient data in front of the agency. PH Health told FDA that the petition and the report “fail to show any pattern of adverse events attributed to BZT,” and the report’s own toxicity evidence is mechanistic and in vitro, not clinical. None of that establishes that benzethonium chloride is harmless at the doses patients receive, and nothing in the file establishes that it is harmful at them either. An approval for the petitioner’s own product does not settle it, and FDA has not said that it does.