Drug Product Compounding Issues Addressed by FDA Panel

Troy Brown, RN

February 24, 2015

The Pharmacy Compounding Advisory Committee of the US Food and Drug Administration (FDA) voted yesterday to add 25 drugs to the list of drug products that may not be compounded under the exemptions provided by the Federal Food, Drug, and Cosmetic Act because they have been withdrawn or removed from the market as a result of their components having been determined to be unsafe or ineffective.

"The agency continually evaluates the safety of drug products, and [the Center for Drug Evaluation and Research's (CDER's)] ongoing commitment to rigorous and continued drug safety evaluation in the postmarket period is reflected in its Safety First initiative, which was launched in 2008 and which outlines CDER's updated policies and procedures to ensure that equal focus and equal attention is given to postmarket drug safety as is given during premarket drug review," said Mwango A. Kashoki, MD, MPH, associate director for Safety, Office of New Drugs, Immediate Office, CDER, FDA.

The committee voted unanimously to add 24 drugs to the list of drugs that may not be compounded: all drug products containing alatrofloxacin mesylate, aminopyrine, astemizole, bromfenac sodium (except ophthalmic solutions), cerivastatin sodium, cisapride, all parenteral drug products containing esmolol HCl that supply 250 mg/mL of concentrated esmolol per 10-mL ampule, gatifloxacin (except ophthalmic solutions), grepafloxacin, methoxyflurane, novobiocin sodium, pemoline, pergolide mesylate, phenylpropanolamine, propoxyphene, rapacuronium bromide, rofecoxib, sibutramine hydrochloride, tegaserod maleate, troglitazone, trovafloxacin mesylate, valdecoxib, all extended-release drug products containing oxycodone hydrochloride that have not been determined by the FDA to have abuse-deterrent properties, all drug products containing polyethylene glycol 3350, sodium chloride, sodium bicarbonate, and potassium chloride for oral solution, and 10 mg or more of bisacodyl delayed-release tablet.

The committee also voted 11 to 1 in favor of adding all drug products containing etretinate to the list.

The committee voted unanimously to update the current entry of "Adenosine phosphate: All drug products containing adenosine phosphate" to state, "All drug products containing adenosine 5'-monophosphate (AMP), adenosine 5'-diphosphate (ADP), and adenosine 5'-triphosphate (ATP)."

The committee voted 9 to 2 (1 no-vote) in favor of adding all oral drug products containing chloramphenicol to the list.

Chloramphenicol for injection is approved by the FDA and is still marketed in the United States. It has a boxed warning because of an increased risk for serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, and granulocytopenia). Aplastic anemia that later terminated in leukemia has also been attributed to chloramphenicol for injection. Published literature suggests the risk for aplastic anemia is higher with the oral formulation.

Other less toxic and more efficacious antibacterial drugs are available.

Bulk Drug Substance List

The committee discussed proposed criteria for developing the list of bulk drug substances that may be used to compound drug products according to section 503A of the Federal Food, Drug, and Cosmetic Act, even though they are neither the subject of a US Pharmacopeia or National Formulary monograph nor components of drugs approved by the FDA.

The proposed criteria are:

  1. the physical and chemical characterization of the substance;

  2. any safety issues raised by the use of the substance in compounded drug products;

  3. the historical use of the substance in compounded drug products, including info about the medical condition or conditions the substance has been used to treat and any references in peer-reviewed medical literature; and

  4. the available evidence of effectiveness or lack of effectiveness of a drug product compounded with the substance, if any such evidence exists.

The FDA considers no single criteria to be dispositive.

Thymol Iodide Added to Bulk List

The committee voted (9 yes, 2 no, 2 no-vote) to place thymol iodide on the list of bulk drug substances that can be used in pharmacy compounding in accordance with section 503A of the FD&C Act ("the 503A bulk list").

Thymol iodide is as an absorbent and protective agent with antimicrobial properties. It is used for topical treatment of ulcerations and various skin infections, as well as dental root filling. Plastic surgeons apply thymol iodide powder after face peeling, and iodized talc is used for pleurodesis in patients with pleural effusions.

There is limited safety information available.

"I think that there is an unusual niche for this and that it's effective," said voting committee member John J. DiGiovanna, MD, staff clinician, DNA Repair Section, Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Silver Protein Mild Not Added to Bulk List

The committee voted unanimously not to place silver protein mild on the 503A bulk list.

Silver protein mild, also known as mild silver protein, is an antiinfective used for ophthalmic purposes. Its most widely known product, Argyrol (Argyrol Pharmaceuticals), was first marketed in 1902. There are no formal safety pharmacology studies of silver protein mild in the published literature. Silver protein mild can cause argyrosis, a deposit of silver in the conjunctiva, lacrimal sac, cornea, and lens that results in bluish-black pigmentation. Argyrosis is permanent and usually does not cause visual acuity impairment but can impair night vision.

There are numerous alternative approved products for ophthalmic antiinfective use.

"It didn't meet any of the four criteria [for evaluating nominated substances]," said voting committee member Jürgen Venitz, MD, PhD, committee chairperson and associate professor, Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond.

In the committee meeting on the Withdrawn or Removed List, one committee member was recused from discussing and voting on one drug product, another committee member was recused from discussing and voting on three drug products, and another committee member was recused from discussing and voting on one drug product because of conflicts of interest. The remaining committee members disclosed no relevant financial relationships. In the committee meeting on the bulk list, two committee members were recused from discussing and voting on one drug product and one committee member was recused from discussing and voting on one drug product.

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