Safety Risks Associated with Certain Bulk Drug Substances Nominated for Use in Compounding
Sign up for email alerts on Compounding
Category 2 of the Bulk Substances Nominated Under Sections 503A or 503B of the Federal Food, Drug, and Cosmetic Act
FDA finalized two guidances clarifying the agency’s proposed policies concerning the use of certain bulk drug substances in compounding by state-licensed pharmacies, federal facilities, and licensed physicians (under section 503A), and by outsourcing facilities (under section 503B):
- Guidance for Industry, Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A of the Federal Food, Drug, and Cosmetic Act
- Guidance for Industry, Interim Policy on Compounding Using Bulk Drug Substances Under Section 503B of the Federal Food, Drug, and Cosmetic Act
The guidance documents describe three categories of nominated bulk drug substances. The bulk drug substances in category 2 were nominated for use in compounding under sections 503A or 503B with sufficient supporting information for FDA to evaluate them, but they raise significant safety risks. FDA would consider taking action against a compounder or outsourcing facility for compounding drug products with bulk drug substances listed in category 2 under its general enforcement policies.
Summary of the Safety Risks
|
Category 2 substance |
Nominated with sufficient information under 503A or 503B or both |
Date added to Category 2 |
Safety risks |
|---|---|---|---|
|
503A |
July 30, 2018 |
The use of cesium poses significant safety risks (e.g., heart toxicity) and is potentially associated with death. Cesium chloride (CsCl) can cause irregular heartbeats, also called arrhythmias. There have been reports of humans experiencing serious heart problems after taking CsCl. CsCl is associated with a lower blood level of potassium, which is a mineral that is essential to normal heart function. |
|
|
503B |
October 5, 2022 |
Chloral hydrate presents significant safety risks related to dosing errors, oversedation, and other adverse events including death, especially in the pediatric population. |
|
|
503A |
October 27, 2015 |
Domperidone is associated with a serious risk of life-threatening cardiac arrhythmias and sudden cardiac death in all populations, including healthy lactating women. Domperidone is transferred into human breast milk, but it is unknown to what extent domperidone in breast milk is absorbed by the breastfed infant and what the resulting drug levels and drug side effects in the exposed infant would be. Domperidone is available to treat certain gastrointestinal conditions that are refractory to standard treatment under an expanded access investigational new drug (IND) program. |
|
| Edetate disodium | 503B | October 12, 2022 | Edetate disodium poses significant safety risks due to medical providers inadvertently interchanging edetate disodium with edetate calcium disodium. In a Federal Register notice published June 12, 2008, FDA withdrew “approval of one new drug application (NDA) and two abbreviated new drug applications (ANDAs) for edetate disodium injection.” The notice stated, “there have been cases where children and adults have died when they were mistakenly given edetate disodium instead of edetate calcium disodium (calcium disodium versenate) or when edetate disodium was used for indications other than those approved by FDA.” |
|
503A; 503B |
June 9, 2016 |
Germanium sesquioxide is likely to be contaminated with highly toxic inorganic forms of germanium salts which can be toxic to the kidneys. Germanium has resulted in nephrotoxicity (kidney injury) and death, even at recommended use levels. |
|
| Ibutamoren mesylate | 503B | December 29, 2022 | Ibutamoren mesylate poses significant safety risks due to the potential for congestive heart failure in certain patients. The Agency is aware of a randomized, placebo-controlled trial assessing ibutamoren mesylate for the treatment of patients recovering from hip fracture that “was terminated early due to a potential safety signal of congestive heart failure.” |
| Neomycin sulfate (all parenteral drug products containing neomycin sulfate except when used for ophthalmic or otic use or in combination with polymyxin B sulfate for irrigation of the intact bladder) |
503B |
October 12, 2022 | There is a significant safety risk that “systemic exposure to neomycin sulfate, whether resulting from intravenous or IM administration, or resulting from absorption after instillation in or irrigation of body cavities, structures or spaces, or from use in wet dressings may cause nephrotoxicity, irreversible ototoxicity (both auditory and vestibular) Neo, and neuromuscular blockade which may result in muscular paralysis or respiratory failure.” |
|
Quinacrine HCl for intrauterine administration |
503A; 503B |
503A: June 9, 2016 503B: June 7, 2021 |
Quinacrine HCl is a known mutagen (causes changes in the DNA of a cell) and is associated with serious adverse reactions such as aplastic anemia, hepatitis, severe dermatitis, exacerbation or worsening of psoriasis, and psychosis. Safety risks associated with intrauterine administration of quinacrine HCl (e.g., for female sterilization) include increased risk for life-threatening reproductive tract malignancies. |