Three years has come and gone since FDA published its Federal Register Notice (here) requiring drug companies to reformulate their acetaminophen (APAP)-containing combination drug products to contain no more than 325mg of APAP per dosage unit. FDA gave manufacturers three years to make the change or face withdraw of approval of their applicants. In an announcement posted at the very end of the day yesterday, FDA gave final notice that “[I]n the near future we intend to institute proceedings to withdraw approval of prescription combination drug products containing more than 325 mg of acetaminophen per dosage unit that remain on the market.”
FDA is concerned about the potential for severe liver damage from taking too much APAP. Limiting the strength of APAP to 325mg per dosage unit will still permit dosing of up to two dosage units (650mg). The maximum single dose cited for APAP in FDA’s OTC Tentative Final Monograph (TFM) is 1000mg with a total maximum dose not to exceed 4000mg. Patients taking APAP combinations, which typically include opioids for pain, may increase dosing (number of dose units or frequency of dosing) without prescriber knowledge due to lack of adequate pain control. Having APAP-containing combination products a with lower APAP dose of 325mg (as opposed to 500mg, 650mg or even 770mg) may help mitigate chances for liver damage. This may also help in a situation where the patient unknowingly took more than one APAP containing product or drinks alcohol when taking APAP.
The FDA notice (here) recommends that health care professionals begin writing prescriptions for the lower strength product and that pharmacists contact prescribers to suggest that the lower dose products be used. FDA does not plan to initiate recall of product containing a higher amount of APAP already in the distribution system, but expects that firms will have discontinued distribution of product under their control that does not comply with the new strength requirements as of yesterday.
It should be noted that this does not cover OTC APAP products which may continue to be marketed at strengths higher then 325mg (most notably 500mg). FDA may eventually reconsider changes to the OTC products or revise the TFM prior to issuing the final OTC Monograph covering this drug. This would involve Comment and Rulemaking activities, so there will be plenty of notice if more changes are coming down the road. We are certain that FDA will be monitoring reports of liver damage from both OTC and prescription products containing APAP and, if a reduction in adverse incidents is not observed, it is surmised that efforts to reduce the amount of APAP in OTC available products may come under greater scrutiny.
Firms that have not taken action to request withdrawal of applications not in compliance with the Federal Register Notice will likely be receiving a letter from FDA (here). Take action now before FDA does!