Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks

Category 2 of the Bulk Substances Nominated Under Sections 503A or 503B of the Federal Food, Drug, and Cosmetic Act

Bulk drug substances used in compounding may present significant safety risks. FDA has identified potential significant safety risks when reviewing nominations for bulk drug substances proposed to be included on the 503A or 503B bulks lists. Such bulk drug substances may appear in category 2 under the following guidance documents:

The agency also has identified potential significant safety risks associated with certain bulk drug substances that do not appear in category 2 under the interim policies above. A bulk drug substance that FDA has identified as presenting a potential significant safety risk might not appear in category 2 because, for example, its nomination was withdrawn.

Bulk drug substances under category 2 of the interim policies

Bulk drug substance	503A category 2, 503B category 2, or both	Date added to category 2	Potential significant safety risks
BPC-157	503A	September 29, 2023	Compounded drugs containing BPC-157 may pose risk for immunogenicity for certain routes of administration and may have complexities with regard to peptide-related impurities and active pharmaceutical ingredient (API) characterization. FDA has identified no, or only limited, safety-related information for the proposed routes of administration. Therefore, the agency lacks sufficient information to know whether the drug would cause harm when administered to humans.
Cathelicidin LL-37	503A	September 29, 2023	Compounded drugs containing cathelicidin LL-37 may pose risk for immunogenicity for certain routes of administration and may have complexities with regard to peptide-related impurities and API characterization. FDA lacks sufficient safety-related information regarding cathelicidin LL-37 to know whether the drug would cause harm when administered to humans. Nonclinical research findings suggest detrimental effects on male reproduction and that this drug can be protumorigenic in some tissues.
Cesium chloride	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.
Chloral hydrate	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.
Diethylstilbestrol	503B	August 21, 2023	Diethylstilbestrol is associated with cancer of the breast in women who were exposed while pregnant and clear cell adenocarcinoma in the vagina and cervix of women who were exposed in utero. A positive association has been observed between exposure to diethylstilbestrol and cancer of the endometrium, and between in-utero exposure to diethylstilbestrol and squamous cell carcinoma of the cervix and cancer of the testis.
Dihexa acetate	503A	September 29, 2023	FDA has not identified any human exposure data on drug products containing dihexa acetate administered via any route of administration. FDA lacks important information regarding any safety issues raised by dihexa acetate, including whether it would cause harm if administered to humans.
Domperidone	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 (except for ophthalmic use)	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.”
Emideltide (DSIP)	503A	September 29, 2023	Compounded drugs containing emideltide may pose risk for immunogenicity for certain routes of administration and may have complexities with regard to peptide-related impurities and API characterization. FDA has not identified safety-related information regarding emideltide for the proposed route of administration. Therefore, the agency lacks sufficient information to know whether the drug would cause harm if administered to humans.
Epitalon	503A	September 29, 2023	Compounded drugs containing epitalon may pose risk for immunogenicity for certain routes of administration due to the potential for aggregation and peptide-related impurities. FDA has not identified safety-related information regarding epitalon for the proposed route of administration. Therefore, the agency lacks sufficient information to know whether the drug would cause harm if administered to humans.
Germanium sesquioxide	503A	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.
GHK-Cu (for injectable routes of administration)	503A	September 29, 2023	Compounded injectable drugs containing GHK-Cu may pose risk for immunogenicity due to the potential for aggregation and peptide-related impurities. There are limited data in humans to inform safety-related considerations.
Growth hormone releasing peptide-2 (GHRP-2) (for injectable and nasal routes of administration)	503B	September 29, 2023	Compounded drugs containing GHRP-2 for injectable and nasal administration may pose risk for immunogenicity due to the potential for aggregation and peptide-related impurities. GHRP-2 also contains an unnatural amino acid, which adds to the complexity of peptide characterization. FDA is aware of reports of serious adverse advents in patients who received GHRP-2, including increased insulin requirement to maintain the blood glucose level, death of critically ill study subjects, infection and pancreatitis, though causality has not been established.
Growth hormone releasing peptide-6 (GHRP-6)	503B	September 29, 2023	Compounded drugs containing GHRP-6 may pose risk for immunogenicity for certain routes of administration due to the potential for aggregation and peptide-related impurities. FDA has identified limited safety-related information, but the available data reveal safety concerns including potential effect on cortisol and increase in blood glucose due to decreases in insulin sensitivity.
Ibutamoren mesylate	503A; 503B	503A: September 29, 2023 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.”
Ipamorelin acetate	503B	September 29, 2023	Compounded drugs containing Ipamorelin acetate may pose risk for immunogenicity for certain routes of administration due to the potential for aggregation or peptide-related impurities. Ipamorelin acetate also contains unnatural amino acids, which add to the complexity of peptide characterization. A study published in literature identified serious adverse events including death when ipamorelin was administered intravenously for improving gastric motility. FDA has not identified safety-related information regarding ipamorelin acetate via certain other injectable routes of administration. Therefore, the agency lacks sufficient information to know whether the drug would cause harm if administered to humans via those routes.
Kisspeptin-10	503A	September 29, 2023	Compounded drugs containing Kisspeptin-10 may pose risk for immunogenicity for certain routes of administration and may have complexities with regard to peptide-related impurities and API characterization. FDA has no, or only limited, safety-related information for the proposed routes of administration. Therefore, the agency lacks sufficient information to know whether the drug would cause harm when administered to humans.
KPV	503A	September 29, 2023	FDA has not identified any human exposure data on drug products containing KPV administered via any route of administration. FDA lacks important information regarding any safety issues raised by KPV, including whether it would cause harm if administered to humans.
Melanotan II	503A	September 29, 2023	Compounded drugs containing Melanotan II may pose risk for immunogenicity for certain routes of administration due to the potential for aggregation or peptide-related impurities. Published case reports discuss serious adverse events including melanoma, posterior reversible encephalopathy syndrome, sympathomimetic toxidrome and priapism.
Mechano growth factor pegylated (PEG-MGF)	503A	September 29, 2023	Compounded drugs containing Mechano Growth Factor Pegylated (PEG-MGF) may pose significant risk for immunogenicity for certain routes of administration and may have complexities with regard to peptide-related impurities and API characterization. FDA has not identified any human exposure data on drug products containing PEG-MGF administered via any route of administration. FDA lacks important information regarding any safety issues raised by PEG-MGF, including whether it would cause harm if administered to humans.
MOTs-C	503A	September 29, 2023	Compounded drugs containing MOTs-C may pose significant risk for immunogenicity for certain routes of administration and may have complexities with regard to peptide-related impurities and API characterization. FDA has not identified, any human exposure data on drug products containing MOTs-C administered via any route of administration. FDA lacks important information regarding any safety issues raised by MOTs-C, including whether it would cause harm if administered to humans.
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 (auditory and vestibular) and neuromuscular blockade which may result in muscular paralysis or respiratory failure.”
Quinacrine hydrochloride 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.
Semax (heptapeptide)	503A	September 29, 2023	Compounded drugs containing semax (heptapeptide) may pose risk for immunogenicity for certain routes of administration due to the potential for aggregation and peptide-related impurities. FDA has no, or limited, safety-related information for proposed routes of administration. Therefore, the agency lacks sufficient information to know whether the drug would cause harm if administered to humans.
Thymosin beta-4, fragment (LKKTETQ)	503A	September 29, 2023	Compounded drugs containing thymosin Beta-4, Fragment (LKKTETQ) may pose risk for immunogenicity for certain routes of administration due to the potential for aggregation as well as peptide-related impurities. FDA has not identified any human exposure data drug products containing Thymosin Beta-4, Fragment. FDA lacks important information regarding any safety issues raised by this drug, including whether it would cause harm if administered to humans.
Tranilast	503B	September 29, 2023	There is a potential risk of serious adverse events associated with systemic absorption of tranilast, including significantly elevated liver enzymes (liver injury), hematologic abnormalities (leukopenia, thrombocytopenia, anemia, hemolytic anemia) and renal failure, which are serious and potentially life threatening.

Other bulk drug substances that may present significant safety risks

Bulk drug substance	Potential significant safety risks
AOD-9604	Compounded drugs containing AOD-9604 may pose significant risk for immunogenicity for certain routes of administration and may have complexities with regard to peptide-related impurities and API characterization. FDA has identified no, or only limited, safety-related information. Therefore, the agency lacks sufficient information to know whether the drug would cause harm when administered to humans. FDA has also identified serious adverse events that may be associated with AOD-9604, though causality is not clear.
CJC-1295	Compounded drugs containing CJC-1295 may pose risk for immunogenicity for certain routes of administration and may have complexities with regard to for peptide-related impurities and API characterization. FDA has identified serious adverse events associated with CJC-1295 including increased heart rate and systemic vasodilatory reaction. Available clinical data are limited.
Ipamorelin acetate, which also appears in the table above because it is in category 2 under the 503B interim policy	Compounded drugs containing Ipamorelin acetate may pose risk for immunogenicity for certain routes of administration due to the potential for aggregation or peptide-related impurities. Ipamorelin acetate also contains unnatural amino acids, which add to the complexity of peptide characterization. A study published in literature identified serious adverse events including death when ipamorelin was administered intravenously for improving gastric motility. FDA has not identified safety-related information regarding ipamorelin acetate via certain other injectable routes of administration. The agency lacks sufficient information to know whether the drug would cause harm if administered to humans via those routes.
Selank acetate (TP-7)	Compounded drugs containing selank acetate may pose risk for immunogenicity for certain routes of administration due to the potential for aggregation and peptide-related impurities. FDA lacks important information regarding any safety issues raised by selank acetate administered to humans.
Thymosin-alpha 1 (Ta1)	Compounded drugs containing thymosin-alpha-1 (Ta1) may pose significant risk for immunogenicity for certain routes of administration and may have complexities with regard to peptide-related impurities and API characterization. The safety-related information is inadequate for the agency to sufficiently understand the extent of any safety issues raised by the proposed compounded drug.