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Ipamorelin Side Effects: Delayed-Onset Adverse Events Explained

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At a glance

  • FDA status / Not approved; no approved dose [1]
  • Dosing studied in the ileus trial / 0.03 mg/kg IV twice daily, day 1 to 7 [2]
  • Low potassium in that trial / 12.5% ipamorelin vs 3.4% placebo [1]
  • Insomnia / 10.7% vs 5.2% [1]
  • High blood sugar at discharge / 14.3% vs 8.6% [1]
  • FDA stated concern / GH-label risks such as fluid retention, glucose intolerance and intracranial hypertension [1]
  • Compounding status / Category 2, may present significant safety risks, for outsourcing facilities [3]

Are delayed side effects of ipamorelin known?

Not from human data. The published ileus trial gave ipamorelin intravenously from postoperative day 1 to 7 or discharge, and its safety reporting covers that window [2][1]. FDA's October 2024 review identified only one published ileus study [1].

What the 7-day ileus trial recorded

The trial enrolled 117 adults undergoing small or large bowel resection and analyzed 114; they received 0.03 mg/kg ipamorelin or placebo intravenously twice daily from postoperative day 1 to 7 or discharge [2]. Any treatment-emergent adverse event was reported in 87.5% of ipamorelin patients and 94.8% of placebo patients [2]. Specific events were more frequent on ipamorelin in FDA's summary: low potassium in 12.5% versus 3.4%, insomnia in 10.7% versus 5.2%, high blood sugar at discharge in 14.3% versus 8.6%, and serious adverse events in 17.9% versus 15.5% [1]. Two ipamorelin-treated patients died of surgical complications after bowel surgery for colon cancer with an anastomotic leak; FDA said it is unclear whether the deaths were related to ipamorelin but that they raise safety concerns [1].

What FDA says about GH and IGF-1 risks

FDA's review notes that ipamorelin stimulates the GH and IGF-1 axis and that it may carry the risks listed on approved growth hormone labels: neoplasm, glucose intolerance and diabetes, intracranial hypertension, fluid retention, hypothyroidism, pancreatitis, and others. It adds that, like the approved GH stimulator macimorelin, ipamorelin might prolong the QT interval, and that FDA found no data showing it would not [1]. FDA raises these as possible GH-related risks for ipamorelin, not as a list of events proven to occur in its trial.

Possible immune reactions

FDA's stated concern for compounded ipamorelin is possible immunogenicity (an immune reaction) for certain routes of administration, from aggregation and peptide-related impurities, plus unnatural amino acids that complicate characterization [3]. The same FDA page cites a study that identified serious adverse events including death when ipamorelin was given intravenously to improve gastric motility, and states that FDA has not identified safety-related information for other injectable routes [3].

What other human studies exist

Only intravenous dosing has been studied in people: 0.03 mg/kg twice daily in the ileus trial, and single 15-minute infusions of 4.21 to 140.45 nmol/kg in healthy male volunteers, where the terminal half-life was about 2 hours and GH rose in a single peak about 0.67 hours after the infusion [2][4]. FDA found no human pharmacokinetic, safety or efficacy data for subcutaneous ipamorelin [1]. In the ileus trial, median time to a tolerated solid meal was 25.3 hours on ipamorelin versus 32.6 hours on placebo, a difference that was not significant (p=0.15), and development was reportedly discontinued [2][1]. In October 2024, FDA's Pharmacy Compounding Advisory Committee voted 0 yes, 12 no, 1 abstention on both ipamorelin free base and ipamorelin acetate, citing a lack of information supporting safety and efficacy [5]. FDA lists ipamorelin acetate in category 2, bulk substances that may present significant safety risks, for outsourcing facilities; it was added September 29, 2023 and is still listed [3][6].

Frequently asked questions

How soon after starting ipamorelin do side effects appear?
The published human data do not establish timing beyond the postoperative ileus trial, which recorded adverse events during days 1 to 7 of twice-daily intravenous dosing. In that trial, low potassium, insomnia and high blood sugar at discharge were each more frequent on ipamorelin than on placebo [1][2].
Does ipamorelin cause water retention?
FDA lists fluid retention among the risks on approved growth hormone labels that ipamorelin may carry, because it stimulates the GH and IGF-1 axis, and FDA found no data showing it would not [1].
Can ipamorelin raise blood sugar?
In the ileus trial, high blood sugar at discharge was reported in 14.3% of ipamorelin patients versus 8.6% on placebo [1]. FDA also lists glucose intolerance and diabetes among the growth hormone label risks it says could apply to a GH-axis stimulator [1].
Does ipamorelin affect thyroid function?
In swine, ipamorelin did not change FSH, LH, prolactin or TSH levels, and most of the selectivity claims come from that animal work [7]. FDA lists hypothyroidism among the approved growth hormone label risks it says could apply, and found no data showing they would not [1].
Is there long-term safety data for ipamorelin?
The published human studies used intravenous dosing only [1]. In October 2024, FDA's Pharmacy Compounding Advisory Committee voted 0 yes, 12 no, 1 abstention against adding it to the pharmacy bulks list, citing a lack of information on safety and efficacy [5].

References

  1. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  2. Beck DE, Sweeney WB, McCarter MD, Ipamorelin 201 Study Group. Prospective, randomized, controlled, proof-of-concept study of the Ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients. Int J Colorectal Dis. 2014;29(12):1527-34. Prospective, randomized, controlled, proof-of-concept study of the Ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients
  3. Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks | FDA. Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks | FDA
  4. Gobburu JV, Agersø H, Jusko WJ, Ynddal L. Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharm Res. 1999;16(9):1412-6. Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers
  5. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  6. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  7. Raun K, Hansen BS, Johansen NL, Thøgersen H, Madsen K, Ankersen M, et al. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998;139(5):552-61. Ipamorelin, the first selective growth hormone secretagogue
Evidence overview for Ipamorelin Side Effects: Delayed-Onset Adverse Events Explained