Evidence review: Open Peptide Project (verified against primary PubMed, ClinicalTrials.gov & FDA records) · Last checked 2026-10-27. ← Back to Evidence Library

Known peptide drug interactions and high-risk contraindications

Name: Known peptide drug interactions and high-risk contraindications
Published: 2026-10-27

Label-documented interactions: oral drugs on GLP-1s, low blood sugar with insulin or sulfonylureas, bremelanotide with naltrexone, methylene blue serotonin syndrome, and pregnancy

Evidence verdict: Regulatory: every interaction here comes from a current FDA-approved label. Interactions for unapproved peptides are largely unstudied. [3, 1, 5, 4]

Last reviewed: Oct 27, 2026

In 30 seconds

Tirzepatide and birth-control pills: labels advise people on oral hormonal contraceptives to switch to a non-oral method, or add a barrier method, for 4 weeks after starting and after each dose increase. [1, 2] [Regulatory]
GLP-1 drugs and other oral medicines: slower stomach emptying can change absorption. Labels advise monitoring drugs with a narrow therapeutic index, such as warfarin, and the oral semaglutide tablet raised levothyroxine exposure by 33%. [1, 3] [Regulatory]
Methylene blue carries a boxed warning for serious or fatal serotonin syndrome with SSRIs, SNRIs, MAOIs and opioids. Bremelanotide is not serotonergic, but it can sharply reduce oral naltrexone levels. [4, 5] [Regulatory]
Pregnancy: stop Wegovy at least 2 months before a planned pregnancy, and stop Zepbound when pregnancy is recognized. Tesamorelin is contraindicated in pregnancy. FDA no longer uses letter categories such as "Category X". [3, 1, 6, 7] [Regulatory]

GLP-1 and dual-incretin drugs: absorption of oral medicines

Semaglutide delays gastric emptying and so may affect the absorption of other oral medicines. In an interaction study with the semaglutide tablet, levothyroxine exposure rose 33%, and the label advises monitoring oral medicines taken at the same time. [3] [Regulatory] The tirzepatide labels advise monitoring patients on oral drugs that depend on threshold concentrations or have a narrow therapeutic index, such as warfarin. [1, 2] [Regulatory]

Tirzepatide and oral contraceptives

Both tirzepatide labels (Zepbound and Mounjaro) advise patients using oral hormonal contraceptives to switch to a non-oral method, or add a barrier method, for 4 weeks after starting and for 4 weeks after each dose escalation. They state that non-oral hormonal contraceptives should not be affected. [1, 2] [Regulatory] This page does not advise on contraception choice; discuss it with a prescriber.

Low blood sugar with insulin or sulfonylureas

GLP-1 drug labels warn that combining them with insulin or an insulin secretagogue (such as a sulfonylurea) may raise the risk of hypoglycemia, including severe hypoglycemia. A prescriber may need to lower the other drug, and patients should learn the signs of low blood sugar. [3, 1] [Regulatory] Growth-hormone-axis peptides push the other way, raising glucose, which matters for people on diabetes medicines (see the GH secretagogue guide). [6, 8] [Regulatory, Controlled study]

Methylene blue: serotonin syndrome

The ProvayBlue label carries a boxed warning: methylene blue may cause serious or fatal serotonin syndrome when used with serotonergic drugs and opioids. It says to avoid combining it with SSRIs, SNRIs, MAOIs and opioids. [4] [Regulatory] Methylene blue is not a peptide, but it is often sold alongside peptides. See the methylene blue page.

Bremelanotide (Vyleesi, PT-141)

Bremelanotide is a melanocortin receptor agonist, not a serotonergic drug. Its label documents two interactions. It may slow gastric emptying and reduce the absorption of oral drugs that need threshold concentrations, and it may significantly lower exposure to oral naltrexone, so the label says to avoid it with oral naltrexone products used for alcohol or opioid addiction. [5] [Regulatory] It is contraindicated in uncontrolled high blood pressure or known cardiovascular disease, because it transiently raises blood pressure and lowers heart rate after each dose. [5] [Regulatory]

Pregnancy and breastfeeding

Since FDA's Pregnancy and Lactation Labeling Rule, labels no longer use letter categories (A, B, C, D, X). They describe risks in narrative form instead. [7] [Regulatory] Current label language: - Wegovy (semaglutide): because of potential fetal harm, stop at least 2 months before a planned pregnancy, to allow for semaglutide's long half-life. [3] - Zepbound (tirzepatide): may cause fetal harm; stop when pregnancy is recognized. [1] - Egrifta SV (tesamorelin): contraindicated in pregnancy. [6] [Regulatory] No pregnancy safety data exist for unapproved peptides. UNVERIFIED

Other high-risk contraindications from labels

GLP-1 and dual-incretin drugs: personal or family history of medullary thyroid carcinoma, or MEN 2. [3, 1]
Tesamorelin and somatropin: active malignancy. [6, 9]
Methylene blue: G6PD deficiency (risk of hemolysis), per its label. [4] [Regulatory] Unapproved peptides have no label, so their interactions and contraindications are unknown, not absent. Tell every clinician and pharmacist about everything you take.

Evidence levels used on this page

[Regulatory] FDA, USP or WADA primary document or an FDA-approved label. [Controlled study] randomized trial or systematic review of trials. [Observational] surveillance, pharmacovigilance or cohort data. [Lab] analytical, cell or animal work. [Guidance] professional-society guidance. [Policy] Open Peptide Project published policy.

Incretin and GLP-1 drug safety, GH secretagogue risks, PT-141 (bremelanotide), Tirzepatide, Semaglutide

References

ZEPBOUND (tirzepatide) prescribing information, Eli Lilly (NDA 217806). DailyMed/openFDA setid 487cd7e7-434c-4925-99fa-aa80b1cc776b, effective Aug 28, 2026.
MOUNJARO (tirzepatide) prescribing information, Eli Lilly (NDA 215866). setid d2d7da5d-ad07-4228-955f-cf7e355c8cc0, effective Aug 27, 2026.
WEGOVY (semaglutide) injection and tablets, prescribing information, Novo Nordisk (NDA 215256). DailyMed setid ee06186f-2aa3-4990-a760-757579d8f77b, published Jun 30, 2026.
PROVAYBLUE (methylene blue) prescribing information, American Regent (NDA 204630). setid 4f6848e5-35ed-4046-b13c-3032b5ba3232, effective May 28, 2025.
VYLEESI (bremelanotide) prescribing information (NDA 210557). setid f1d0c1b5-2f39-4bad-a6a4-0066e3ad5dcf, effective Nov 13, 2025.
EGRIFTA SV (tesamorelin) prescribing information, Theratechnologies (BLA 022505). setid 3d783378-b02d-4f19-99dd-0fc91a042224, effective Jul 29, 2026.
US FDA. Pregnancy and Lactation Labeling (Drugs) Final Rule (content current as of 03/10/2025). https://www.fda.gov/drugs/labeling-information-drug-products/pregnancy-and-lactation-labeling-drugs-final-rule
Nass R, et al. Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial. Ann Intern Med. 2008. PMID 18981485.
GENOTROPIN (somatropin) prescribing information, Pfizer (BLA 020280). setid ffebf88b-d257-4542-9808-74d9b7167765, effective Aug 4, 2026.

Disclaimer: This page is for education only. It is not medical advice, and it does not endorse using, buying or preparing any unapproved product. Talk to a licensed clinician before you start, stop or change any treatment.