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Proglumide (ATC A02BX06) is an old, now rarely used, non‑selective cholecystokinin (CCK) antagonist whose use in pregnancy and lactation should generally be avoided because of limited modern data and plausible toxicological concerns, especially for breastfed neonates.file+4

Pharmacological profile

Proglumide is classified under ATC code A02BX06 in the group “other drugs for peptic ulcer and gastro‑oesophageal reflux disease.” It is a non‑selective CCK receptor antagonist that reduces gastric secretion and inhibits gastrointestinal motility, historically used as an anti‑ulcer drug and gastroprotective adjuvant. Proglumide is usually administered orally, has moderate bioavailability, and is mainly eliminated via hepatic metabolism followed by renal excretion.drugbank+3

Proglumide is essentially a racemate composed of equal amounts of R‑ and S‑enantiomers. It acts as a prodrug that undergoes hepatic biotransformation to active metabolites with anti‑ulcer, cholinergic, motility‑modulating and delimited opioid receptor agonist activity, particularly at delta‑opioid receptors. Experimental data also suggest modulation of analgesic and euphoric responses to opioids, with prolongation of opioid‑induced anaesthesia and potential central effects mediated via brainstem and trigeminal regions.pmc.ncbi.nlm.nih+1

General toxicity and adverse effects

Historical clinical experience and preclinical data indicate that chronic use of proglumide may cause pancreatic hypertrophy, which contributed to its progressive replacement by safer acid‑suppressive agents. In addition, proglumide’s anticholinergic toxicity has been associated with potentially severe cardiac arrhythmias, including torsade‑like ventricular tachycardia (“torsion de pointes” type), which can be life‑threatening in susceptible patients. Commonly described adverse effects for proglumide include gastrointestinal disturbances (nausea, vomiting, diarrhoea, abdominal pain), dizziness and drowsiness, although these are usually mild and dose‑related.wikipedia+2

Older toxicological descriptions mention a relatively wide therapeutic index but also report a very high oral lethal dose in animals, on the order of tens of grams per kilogram, underscoring that clinically relevant toxicity is more related to specific organ effects (pancreas, heart, CNS) than to acute lethality. Modern phase‑1‑type pharmacokinetic studies in adults suggest that single oral doses of proglumide are generally well tolerated, including in cirrhotic patients, without significant laboratory or clinical toxicity, but these studies did not include pregnant or breastfeeding women or infants.file+1

Reproductive and pregnancy risk

There are no robust, contemporary human pregnancy studies for proglumide; available information is mainly extrapolated from animal data and historic regulatory classifications. Proglumide has been historically placed in FDA pregnancy category C, indicating evidence of adverse effects in animal studies or insufficient human data, so that use in pregnancy should be restricted to situations where potential maternal benefit clearly outweighs fetal risk. As with most non‑essential gastrointestinal drugs, general principles of teratology recommend avoiding proglumide especially in the first trimester, when organogenesis and structural development are most vulnerable to drug‑induced malformations.who+4

In later pregnancy, potential concerns relate to its anticholinergic and central effects (maternal tachyarrhythmias, CNS effects) and possible interference with fetal gastrointestinal or pancreatic development, although direct evidence is lacking. Given the availability of alternative, better‑studied anti‑ulcer and gastro‑oesophageal reflux therapies in pregnancy (e.g. certain H2‑blockers and proton‑pump inhibitors with more reassuring data), proglumide is generally considered obsolete and should not be a first‑line option for pregnant women.pharmaceutical-journal+3

Lactation pharmacokinetics and infant exposure

The molecular mass of proglumide is approximately 334 Da, which is well within the range that favours transfer into human milk. It has an oral bioavailability around 60%, suggesting that any drug ingested via breast milk is likely to be systemically absorbed by the infant to a clinically relevant degree. The reported elimination half‑life of about 24 hours implies a significant potential for accumulation in both maternal plasma and breast milk during repeated dosing, leading to higher steady‑state concentrations in milk.drugbank+2

Based on its low molecular weight, moderate oral bioavailability and relatively long half‑life, it is pharmacokinetically predictable that milk concentrations will be close to maternal plasma levels, particularly with chronic use. Because most medicines with these characteristics reach measurable levels in human milk, and because proglumide lacks specific studies quantifying its milk‑to‑plasma ratio, a cautious worst‑case assumption is that the breastfed infant might receive exposures approaching a fraction of the maternal weight‑adjusted dose. In the context of anticholinergic and central opioid‑modulating properties, this theoretical exposure raises significant safety concerns for neonates and young infants.oamonitor.ireland.openaire+1

Toxicological risk during breastfeeding

From a lactation‑safety standpoint, proglumide combines several unfavourable features: probable efficient transfer into milk, significant oral bioavailability in the infant, long half‑life, and potential for serious toxicities (cardiac arrhythmias, anticholinergic effects, central nervous system modulation and euphoria‑like states). Neonates are particularly vulnerable to anticholinergic toxicity, which can manifest as tachycardia, arrhythmias, feeding difficulties, hyperthermia, and neurological symptoms; in the setting of proglumide exposure via breast milk, such effects would be difficult to predict or monitor safely.synapse.patsnap+3

In addition, the delta‑opioid agonist component of its pharmacology raises the possibility of central nervous system effects in the infant, such as abnormal euphoria‑like behaviour, muscle hyperexcitability and inconsolable crying, although these manifestations remain theoretical in the absence of published case reports. Because safer and well‑characterised alternatives exist for treating maternal peptic ulcer and reflux disease during lactation, expert toxicology‑lactation assessments classify proglumide as completely unsuitable for use in breastfeeding women. In the local toxicological‑lactation classification used on your site, proglumide is placed in lactation risk category IV (“entirely inappropriate for use during lactation”), indicating that its use is contraindicated while breastfeeding.pmc.ncbi.nlm.nih+3

If proglumide exposure has already occurred in a breastfeeding mother, clinical monitoring of the infant for signs of anticholinergic or CNS toxicity (changes in feeding, unusual irritability, muscle hypertonia or hypotonia, and cardiac symptoms) is advisable, and temporary interruption of breastfeeding or switch to formula may be considered depending on dose and duration. However, due to the lack of quantitative milk‑level data or infant case reports, any such management should be individualised and, where possible, guided by consultation with a specialised teratology or lactation‑pharmacology service.stjames+3

Clinical recommendations

• Proglumide should not be initiated as therapy in breastfeeding women, given its unfavourable toxicological profile and the absence of reassuring lactation data. Safer alternatives with established breastfeeding compatibility should be used instead.who+2
• In pregnancy, particularly in the first trimester, proglumide should be avoided unless there is a compelling indication and no safer alternative, in line with general principles for category C drugs and gastrointestinal pharmacotherapy.pharmaceutical-journal+2
• Women of reproductive age who are already taking proglumide and are planning pregnancy, pregnant, or breastfeeding should be reviewed by a clinician to consider transition to modern, better‑studied agents.who+1
• From a public‑health and educational perspective, proglumide serves as an example of an older anti‑ulcer agent whose risk‑benefit balance in reproductive medicine and lactation is unfavourable compared with current standards of care.wikipedia+2