An FDA Warning Letter that Does Not Add Up: OTC Drug Monograph Combination Products With Conflicting Dosing Directions

By Kurt R. Karst –      

Earlier this year, FDA’s Dallas District Office issued a Warning Letter to Sovereign Pharmaceuticals, LLC (“Sovereign”), a pharmaceutical contract manufacturing facility located in Fort Worth, Texas, containing a rather interesting – and quite perplexing – violation tagged under the heading “Unapproved and/or Misbranded Drug Products.”  Specifically, with respect to Sovereign’s Over-the-Counter (“OTC”) cough/cold drug products Certuss, Certuss-D, and Trexbrom, FDA’s Warning Letter states: 

Certuss, Certuss-D, and Trexbrom contain the active ingredient chlophedianol, which is an acceptable antitussive active ingredient.  However, chlophedianol cannot be combined with the particular active ingredients phenylephrine (in the case of Trexbrom) or guaifenesin (in the cases of Certuss and Certuss-D) because there is no way to write adequate directions for use that would meet the dosing direction and dosage limit requirements for each individual active ingredient (21 CFR 341.40).  For example, the monograph states phenylephrine and guaifenesin are to be dosed every 4 hours (21 CFR 341.80(d)(1) and 21 CFR 341.78(d), respectively) and chlophedianol is to be dosed every 6 to 8 hours (21 CFR 341.74 (d)(1)).  Therefore, if chlophedianol is used in combination with either phenylephrine or guaifenesin, there is no way to write directions for use with a dosing interval that works for each of these active ingredients. [(Emphasis added)]

FDA’s statements above that OTC drug products with active ingredient combinations that appear to be permitted under a monograph, but that contain conflicting dosing directions, cannot be lawfully marketed caught our attention because the Agency has said otherwise for decades.  Indeed, FDA’s OTC drug regulations require that when the time intervals for active ingredients conflict, the manufacturer should choose directions for the combination product that do not exceed any maximum dosage limits.  Specifically, FDA’s regulation at 21 C.F.R. § 341.85(d), titled “Labeling of permitted combinations of active ingredients,” and included in the Agency’s OTC drug monograph for cold, cough, allergy, bronchodilator, and antiasthmatic drug products, states:

When the time intervals or age limitations for administration of the individual ingredients differ, the directions for the combination product may not exceed any maximum dosage limits established for the individual ingredients in the applicable OTC drug monograph.

Similar statements appear in other OTC drug monographs at 21 C.F.R. § 333.160(d) (topical antimicrobial drug products), § 346.52(d) (anorectal drug products), § 347.60(d) (skin protectant drug products), § 349.79(d) ophthalmic drug products ), § 352.60(d) (sunscreen drug products), and § 358.760(d) (dandruff drug products).  

What each regulation says in essence is that when the directions for use of an OTC combination drug product results in a conflict in time intervals, the directions should be written to ensure that the maximum dosage limits established under the applicable monograph for the individual ingredients are not exceeded.

Furthermore, with respect to cough/cold drug products, such as those at issue in the Sovereign Warning Letter, FDA has discussed and elaborated on in preambles and policy statements OTC drug product combinations with conflicting directions.  For example, FDA has stated:

The agency has also identified conflicts in that portion of the directions that deal with the lower age limits of use for children’s dosages for some of the combinations identified in § 341.40.  For example, the directions for an OTC antihistamine advises that a doctor be consulted for use in children under 6 years of age, while OTC analgesic-antipyretic ingredients may be given to a child as young as 2 years of age without consulting a doctor.  The agency is concerned that when a combination product containing analgesic-antipyretic and cough-cold ingredients is labeled for use in children of a particular age group that each individual ingredient be generally recognized as safe for use in that particular age group.  Therefore, the agency is proposing that when there is a difference in the directions established for the individual ingredients in a combination drug product, e.g., when the time intervals or age limitations for administration of the individual ingredients differ, the directions for the combination product may not exceed any maximum dosage limits established for the individual ingredients in the applicable OTC drug monograph.  Thus, in the above example, the product can be labeled only for use in children 6 years of age and over. [(53 Fed. Reg. 30,522, 30,554 (Aug. 12, 1988))]

. . . and

The agency believes that an OTC drug product containing diphenhydramine citrate or diphenhydramine hydrochloride that is labeled both as an antitussive and an antihistamine should conform to the same labeling restrictions that apply to combination drug products containing a different antitussive and antihistamine ingredient.  In the tentative final monograph for OTC cough-cold combination drug products, the agency proposed that when there is a difference in the directions established for the individual ingredients in a combination drug product, e.g., when the time intervals or age limitations for administration of the individual ingredients differ, the directions for the combination product may not exceed any maximum dosage limits established for the individual ingredients in the applicable OTC drug monograph (53 FR 30522 at 30554).  Therefore, when diphenhydramine citrate or diphenhydramine hydrochloride is labeled for both antitussive and antihistamine use, the limiting factor for directions for use for both the dosage amount and dosing interval for OTC labeling is the antitussive dosage in Sec. 341.74(d)(1)(iv) and (d)(I)(v).  However, the limiting factor for directions for use for professional labeling is the antihistamine dosage in Sec. 341.90(j) and (k) (21 CFR 341.90(j) and (k), respectively.  As noted above, the Panel believed that the interests of consumers are best served by exposing the user of OTC drug products to the smallest number of ingredients possible at the lowest possible dosage consistent with a satisfactory level of effectiveness. [(60 Fed. Reg. at 10,286, 10,290 (Feb. 23,1995))]

. . . and

The antitussive directions are 5 to 10 mg every hour as needed, while the anesthetic/analgesic directions are 2 to 20 mg every 2 hours.  The agency’s policy is that when there is a difference in the directions established for the individual ingredients in a combination drug product, e.g., when the time intervals or age limitations for administration of the individual ingredients differ, the directions for a combination product may not exceed any maximum dosage limits established for the individual ingredients in the applicable OTC drug monograph (53 FR 30522 at 30554).  This policy also applies when an ingredient is being labeled for dual use in a single product.  Under this rationale, the every 2 hours directions for anesthetic/analgesic use would be controlling.  The problem arises, however, that amounts of menthol from 2 mg up to 5 mg are not monograph dosages for menthol for antitussive use.  Therefore, the agency has determined that appropriate directions for menthol when labeled for both uses in a product is 5 to 10 mg every 2 hours.  [(67 Fed. Reg. 78,158, 78,162 (Dec. 23, 2002))]

Given all of this history, why then would FDA tell Sovereign that there is no way to write adequate directions for use for the combination cough/cold OTC drug products it contract manufacturers that would meet the dosing direction and dosage limit requirements for each individual active ingredient under the monograph?  That’s the truly perplexing part of this story.  Perhaps FDA made the statements in error and has not yet acted to correct them.  If that’s the case, then the uncorrected Warning Letter sends the wrong – indeed, incorrect – message to the OTC drug industry.  Or perhaps there’s more to the story and something is brewing at FDA.  But if that were the case, then one might have expected to see more on the topic over the past 8 months.  So we’re left scratching our heads.