Ipamorelin Side Effects: Incidence Rates Across Clinical Trials

Where the human safety data come from

Ipamorelin's controlled human safety data come from one published trial: a 2014 phase 2 study in adults recovering from bowel surgery, which enrolled 117 patients and analyzed 114 [2]. A separate 1999 study in healthy volunteers described how the peptide is handled by the body and how it releases growth hormone [3]. The 2014 bowel-surgery trial reported adverse-event percentages [1][2]; the volunteer study's published results cover pharmacokinetics and the growth hormone response [3].

A second phase 2 trial of ipamorelin versus placebo after small or large bowel resection was listed with 320 participants, running from April 2011 to May 2014, but no results are posted for it. FDA's October 2024 review identified only one published ileus study, and development of the drug was reportedly discontinued after disappointing phase 2 results [1].

The ileus trial: who was studied and how it was dosed

The trial was multicenter, randomized, double-blind and placebo-controlled, in adults undergoing small or large bowel resection by open or laparoscopic surgery [2]. Patients received ipamorelin 0.03 mg/kg by intravenous infusion twice daily, or placebo, from postoperative day 1 to day 7 or hospital discharge, with safety assessed by adverse-event monitoring and laboratory tests [2].

The main efficacy endpoint, median time to first tolerated solid meal, was 25.3 hours with ipamorelin and 32.6 hours with placebo, a difference that was not statistically significant (p=0.15) [2].

Incidence rates: ipamorelin versus placebo

In FDA's summary of the trial and the published report [1][2]:

• Any treatment-emergent adverse event: 87.5% versus 94.8% [2]
• Low potassium: 12.5% with ipamorelin versus 3.4% with placebo [1]
• High blood sugar at discharge: 14.3% versus 8.6% [1]
• Insomnia: 10.7% versus 5.2% [1]
• Serious adverse events: 17.9% versus 15.5% [1]

Nearly every patient in both arms had at least one adverse event. The overall rate was lower with ipamorelin, while several specific laboratory and symptom events were more frequent with it [1][2].

The two deaths in the ipamorelin arm

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 expects beyond this trial

Because ipamorelin stimulates the growth hormone and IGF-1 axis, FDA said it may carry the risks listed on approved growth hormone labels: neoplasm, glucose intolerance and diabetes, intracranial hypertension, fluid retention, hypothyroidism, pancreatitis and others. Like the approved growth hormone stimulator macimorelin, it may also cause QT prolongation. FDA found no data showing that it would not [1].

FDA also flagged a possible immunogenicity risk for certain routes of administration from aggregation and peptide-related impurities, and noted that ipamorelin contains unnatural amino acids that complicate characterization [4].

What the volunteer study measured

The 1999 pharmacokinetic study tested five infusion rates: 4.21, 14.02, 42.13, 84.27 and 140.45 nmol/kg, each infused over 15 minutes, with eight healthy male volunteers at each dose level [3]. Terminal half-life was about 2 hours, clearance 0.078 L/h/kg and steady-state volume of distribution 0.22 L/kg [3]. Growth hormone rose in a single peak at 0.67 hours and fell to negligible concentrations at every dose [3].

Why these rates do not describe subcutaneous use

The human studies described here dosed ipamorelin intravenously [2][3], and FDA found no human pharmacokinetic, safety or efficacy data for subcutaneous ipamorelin [1]. The ileus trial's rates come from adults recovering from bowel resection who received intravenous ipamorelin at 0.03 mg/kg twice daily [2].

Regulatory status

Ipamorelin is not an FDA-approved drug and is not a component of any FDA-approved product [1]. FDA lists ipamorelin acetate in category 2, its list of bulk substances that may present significant safety risks, for outsourcing facilities; it was added on September 29, 2023 and remains listed [4][6]. In October 2024, FDA's Pharmacy Compounding Advisory Committee voted 0 yes, 12 no, with 1 abstention, on both ipamorelin free base and ipamorelin acetate, citing a lack of information supporting safety and efficacy for growth hormone deficiency and postoperative ileus [7].