October 29, 2013
FDA’s Center for Veterinary Medicine (CVM) is explaining how the approved animal drugs melengestrol acetate, monensin, and tylosin can be combined in animal feed. Melengestrol acetate-monensin-tylosin and melengestrol acetate-monensin combinations are fed to heifers in confinement for slaughter for several approved indications, as listed in the Code of Federal Regulations.
In October 2011, CVM changed the regulations to reflect new supplemental approvals for melengestrol acetate in combination with monensin and tylosin. The previous approvals had allowed melengestrol acetate to be combined with monensin and tylosin, and with monensin alone, in the same top dress, called a “common” top dress. The supplemental approvals amended the regulations to no longer allow for these common top dresses.
CVM is aware that the change to the approvals for melengestrol acetate has caused confusion. The center wants to clarify that, currently, melengestrol acetate can be combined with monensin and tylosin as a Type C medicated feed only as specified in the Code of Federal Regulations (21 CFR 558.342(e)(1)(xi)). Accordingly, melengestrol acetate can only be mixed as a top dress into complete feed containing 10 to 40 grams per ton of monensin and 8 to 10 grams per ton of tylosin at feeding.
The center also wants to clarify that melengestrol acetate and monensin can only be combined by mixing melengestrol acetate as a top dress into complete feed containing 10 to 40 grams per ton of monensin at feeding, as specified in the Code of Federal Regulations (21 CFR 558.342(e)(1)(x)).
What Led to the Change to the Approvals:
The supplemental approvals for melengestrol acetate changed the way medicated feed containing melengestrol acetate can be manufactured. Under the previous approvals, the drug could be combined with other drugs in various ways. One way was to combine melengestrol acetate with one or two other approved animal drugs in a common top dress. The common top dress was then added to a non-medicated feed. Another way was to make a top dress containing only melengestrol acetate. The top dress was then added to a medicated feed which already contained the other approved animal drug, or drugs. CVM approved these combinations before Congress passed the Animal Drug Availability Act (ADAA) of 1996, which means the approvals were based on data from traditional effectiveness studies that showed each component drug contributed to the intended effect of the combination.
But post-ADAA, traditional effectiveness studies are not required for combination products as long as each component drug brings a unique indication to the combination and is already approved for the unique indication.1 Also under the ADAA provisions, each component drug must already be labeled for its intended indication (use) in the combination product. So, if a component drug is approved and labeled for several uses, some of which are different than its intended use, or uses, in the combination product, then the different uses cannot be included in the labeling for the combination product. This is the case for melengestrol acetate when used in a Type C medicated feed.
In October 2009, CVM granted a supplemental approval to Pfizer (now Zoetis), expanding the concentration range for monensin to up to 40 grams per ton in the melengestrol acetate-monensin-tylosin combination. This change was consistent with the approved dose range for monensin when the drug is fed alone to heifers.
To understand how the post-ADAA supplemental approval affected how the three drugs can be combined, it is necessary to know the approved indications for each drug in a Type C medicated feed: (1) melengestrol acetate is only approved in a Type C medicated feed as a top dress, not as a complete feed; and (2) both monensin and tylosin are not approved as a top dress with melengestrol acetate but are approved in a Type C medicated feed as a complete feed. It follows that, because monensin and tylosin are not approved as a top dress with melengestrol acetate, feed companies and feed mills may not manufacture a common top dress containing all three drugs. Instead, melengestrol acetate can only be given as a top dress that is added to medicated feed containing monensin and tylosin. Adding the melengestrol acetate top dress to the medicated feed can only be done “at feeding” on the farm or feedlot. CVM added a new subsection to the existing melengestrol acetate regulations to reflect this approval (21 CFR 558.342(e)(1)(ix)-(xi)).
A supplemental approval for the melengestrol acetate-monensin combination placed similar limitations on that combination. Melengestrol acetate can only be given as a top dress that is added to medicated feed containing monensin. The melengestrol acetate top dress must be mixed with the medicated feed at feeding on the farm or feedlot. Because monensin is not approved as a top dress with melengestrol acetate, feed companies and feed mills may not manufacture a common top dress containing both drugs.
After the 2009 Pfizer supplemental approval, the drug sponsor for the generic copies of these combinations requested the same expanded concentration range for monensin. By law, the labeling for a generic copy must match the labeling for the pioneer product. The supplemental approval changed both the labeling for Pfizer’s pioneer product and the regulations to no longer include the indications for combining melengestrol acetate with monensin and tylosin, and with monensin alone, in a common top dress. Therefore, these indications were removed from the labeling for the generic copies. Because the new, supplemental approvals replaced the previous approvals, CVM also removed the sections of the regulations that allowed for the common top dresses.
To summarize, melengestrol acetate can only be fed to heifers in confinement for slaughter as a top dress which is then added to medicated feed containing monensin and tylosin, or monensin alone, at feeding. Adding the melengestrol acetate top dress to medicated feed containing the other approved animal drug, or drugs, can only be done on the farm or feedlot. A commercial feed company or feed mill cannot manufacture, pack, or ship a complete Type C medicated feed containing a combination of melengestrol acetate, monensin, and tylosin, or melengestrol acetate and monensin.
1 The ADAA provisions are different for combination products containing nontopical antibacterial drugs.