As the FDA’s first ANDA suitability petition coordinator at the time of the initial passage of Hatch-Waxman as well as having been involved for my full ten years at the FDA and 30+ years in industry, I’ve seen a lot of suitability petitions, a lot of responses, and some strange things in my day. I’ve also been involved in many petitions asking the FDA to determine whether a discontinued product was removed from the market for reasons of safety or efficacy. Lately, however, there have been two FDA responses of a type that I’ve never seen before, and I just can’t figure them out.
First was the FDA’s reply to Docket No. FDA-2025-P-2611 (here) in which the FDA made a determination that a request for a strength change for Hydroxyzine Hydrochloride Oral Solution USP, 10 mg/5 mL to a Hydroxyzine Hydrochloride Oral Solution USP, 25 mg/5 mL raised a question of safety because of the differing solution strength.
The Agency says in the petition response that it “has determined that your proposed change in strength raises questions of safety. The proposed change in strength from 10 mg/5 mL to 25 mg/5 mL raises safety concerns due to the 2.5-fold increase in concentration and would introduce new risks of medication errors (i.e., wrong dose/strength and overdose). Specifically, the changes may result in oversedation, cardiac dysrhythmia, hypotension, and seizures.”
Historically, a petition like this would’ve been considered what one might call a “slam dunk” for several reasons. Firstly, the FDA has previously approved several petitions permitting such strength changes for higher concentration of other oral solutions. Secondly, the FDA has approved NDAs for different concentrations of other oral-solution products for the same drug products.
The Hatch-Waxman Act permits labeling of a generic drug product to be different than that of the innovator for certain reasons, for instance, due to patent or exclusivity issues or because a drug product was approved pursuant to an ANDA suitability petition. The FDA argument that there may be medication errors because of the 2.5-fold increase in strength is something that can be handled through additional warnings on the label, which would typically be permitted in labeling of the ANDA. Also, the FDA has ignored the fact that use of the currently approved 10-mg/5-mL strength to achieve higher label-recommended doses of the drug product could introduce a potential for more errors in measurement and administration in instances when a higher dose of hydroxyzine is required. Patients would need to accurately measure 2.5 teaspoonfuls of the 10-mg/5-mL product to achieve the dose that one 5-mL dose of the 25-mg/5-mL proposed product would provide, potentially leading to dosing errors due to misadministration. With label-recommended doses of up to 50 mg to 100 mg four times a day, the dosing error could be compounded.
Having a 25-mg/5-mL oral solution would also decrease the volume of drug product that must be ingested to reach the required dose. How many times, when you’ve been cooking soup, have you lost track of the number of cups of chicken stock that you’ve already added to the pot? Can you imagine needing to measure out and give 50 mL of the 10-mg/5-mL product to achieve a dose of 100 mg four times a day? Well, the counter argument is, why not just give a 100-mg tablet? But, if the patient has dysphasia or an NG tube, that may not be practical with a solid oral dosage form. The approval of a 25-mg/5-mL oral solution would (in the instances noted above) lessen the chance for administration and dosing errors, as well as greatly decrease the volume of the required dose.
The second petition response that floored me was related to Docket FDA-2025-P-7370 (here), which relates to a request by the petitioner for the FDA to make a determination that the drug product, Mysoline (primidone) suspension, 250 mg/5 mL, approved under new drug application 010401, was not withdrawn from sale for reasons of safety or effectiveness. Again, another petition that what one might call a slam dunk. However, the FDA responded that “[a]fter considering the citizen petition and reviewing Agency records and based on the information we have at this time, FDA has determined under § 314.161 that MYSOLINE (primidone) suspension, 250 mg/5 mL, was withdrawn for reasons of safety or effectiveness.”
The Agency described its rationale for its determination that the product was removed for safety in a January 2, 2026 Federal Register notice (here) when it stated that “MYSOLINE (primidone) suspension, 250 mg/5 mL, was discontinued in 2001 after antimicrobial effectiveness testing raised concerns about potential microbial contamination, in particular with Pseudomonas aeruginosa. As a scientific matter, before MYSOLINE (primidone) suspension, 250 mg/5 mL, could be considered for reintroduction to the market, a reformulation would be required including establishment of preservative content acceptance criteria and correlation with passing antimicrobial effectiveness testing results. The NDA holder for MYSOLINE (primidone) suspension, 250 mg/5 mL, would have to demonstrate the safety and effectiveness of the reformulated product. At this time, no new formulation has been approved for MYSOLINE (primidone) suspension, 250 mg/5 mL. Accordingly, under § 314.162 the Agency will remove MYSOLINE (primidone) suspension, 250 mg/5 mL, from the list of drug products published in the Orange Book. FDA will not accept or approve ANDAs that refer to this drug product.”
The issue that the FDA identified with the Mysoline suspension product did not relate to the underlying safety or efficacy of the drug itself, but rather to characteristics of the preservative system employed by the innovator’s formulation. There have been instances, even in existing NDAs or ANDAs, when firms were required to revise their formulation or change the preservative to better ensure that the preservative achieves the desired antimicrobial effect. However, this does not, in my opinion, speak to the underlying safety of efficacy of the drug itself.
Because there is no requirement that the formulation in an ANDA for an oral suspension be the same as that of the reference listed drug, an ANDA sponsor could formulate it with a different preservative system to address the microbiological concerns and, as long as the difference in the inactive ingredients used in the new preservative system was used in previously FDA-approved products and these ingredients do not exceed the maximum daily intake in those other products. If the ANDA met all other approval requirements, there is no reason that the ANDA could not be approved. The failure of the innovator to adequately resolve the antimicrobial preservative issue found in the Mysoline product should not preclude acceptance of an ANDA as this is just a CMC issue and not even vaguely a safety issue. If an OGD review of the ANDA found that the antimicrobial issue was not adequately resolved to the Agency’s satisfaction, the OGD would then refuse to approve the ANDA.
I’m not sure whether it’s the exodus of institutional knowledge that occurred over the past year, with so many senior FDA staff members leaving impacting the direction of these decisions, or whether there has been some wholesale change in precedence for these petition responses, but something has certainly changed at the Agency with regard to decisions on some of these types of petitions.
