The FDA has identified potential significant safety risks for several bulk drug substances proposed for use in compounded drugs, among them the peptides growth hormone releasing peptide-2 (GHRP-2) and ipamorelin acetate. The agency cited reports of serious adverse events, including death, while stating that causality has not been established for the GHRP-2 cases.

Both compounds are growth hormone secretagogues, meaning they are intended to prompt the body's own release of growth hormone rather than supply it directly. Neither is an approved drug product, which is why they turn up in compounding pharmacies and, downstream, in the gray market that advertises them to consumers.

What category 2 means

Under the FDA's interim policies for bulk substances used in compounding, substances judged to carry potential significant safety risks are placed in category 2. The agency's current list covers substances either remaining in or withdrawn from that category, and both GHRP-2 and ipamorelin acetate appear on it.

The manufacturing problem

For compounded GHRP-2 intended for injectable or nasal use, the FDA pointed to possible immunogenicity tied to aggregation and peptide-related impurities. It also flagged the difficulty of characterizing a peptide that contains an unnatural amino acid, and listed the same two concerns for ipamorelin acetate.

That is a quieter finding than the death reports, and arguably the more consequential one for anyone buying compounded peptides. If a substance is hard to characterize in a controlled setting, the odds of knowing what is in an unregulated vial are not good.

The adverse events

The FDA said it is aware of serious adverse events in patients who received GHRP-2, including increased insulin requirements to maintain blood glucose, infection, pancreatitis and death among critically ill study subjects. For ipamorelin, the agency cited a published study reporting serious adverse events, including death, when the peptide was given intravenously to improve gastric motility.

The agency was careful about the gaps. It said it has not identified safety-related information for ipamorelin acetate through certain other injectable routes, and therefore lacks sufficient information to determine whether those routes would cause harm.

Other peptides named

The list extends past those two. The FDA cited possible effects on cortisol and increased blood glucose from reduced insulin sensitivity with growth hormone releasing peptide-6, and a potential for congestive heart failure with ibutamoren mesylate.

On ibutamoren, the agency noted that a randomized, placebo-controlled trial in patients recovering from hip fracture was terminated early because of a potential safety signal for congestive heart failure. A stopped trial is about as clear a data point as this corner of the field produces.

Bottom line

The FDA has not concluded that these peptides caused the deaths reported, and it said as much regarding GHRP-2. What it has concluded is that the risks are significant enough to keep these substances in the category reserved for compounds it is not comfortable with, and the characterization problems it describes are unlikely to be solved by the suppliers selling them.