LACTOLOGY FOUNDATION

Pepsin and Acid Preparations

ATC code: A09AC01
ATC designation: Pepsin and acid preparations
Pharmacological/therapeutic group: Digestives, including enzymes; enzyme and acid preparations, combinations

1. ATC Classification and Pharmacological Profile

A09AC01 is classified within the WHO Anatomical Therapeutic Chemical (ATC) system under A — Alimentary tract and metabolism; A09 — Digestives, including enzymes; A09A — Digestives, including enzymes; A09AC — Enzyme and acid preparations, combinations. The current WHO ATC/DDD Index designates A09AC01 as “pepsin and acid preparations.” No Defined Daily Dose (DDD) is assigned.

The class comprises combination digestive preparations in which the proteolytic enzyme pepsin is administered together with an acidifying component. Historically and in currently encountered formulations, the acid component may be supplied by compounds such as betaine hydrochloride; however, composition and strength are product-dependent and the lactation assessment of a specific medicinal product should therefore take its complete formulation into account. A historical example of an A09AC01 preparation contained pepsin together with betaine hydrochloride, while regulatory databases also document other pepsin/acid combinations.

Pepsin is an aspartic protease normally present in gastric juice. Its principal pharmacological role in these preparations is local intragastric proteolysis. The acidic component lowers gastric pH, thereby providing an environment favourable for pepsin activity and, in principle, compensating for deficient gastric acidity. The pharmacodynamic action of the combination is consequently predominantly luminal rather than systemic.

The acidifying effect of betaine hydrochloride has been demonstrated experimentally in humans. In healthy volunteers with proton-pump-inhibitor-induced hypochlorhydria, betaine hydrochloride produced rapid but temporary gastric re-acidification. In one study, gastric pH fell from approximately 5.2 to 0.6, with a mean onset to pH <3 of about 6 minutes and a duration below pH 3 of approximately 73 minutes. These findings demonstrate the local acidifying pharmacology of this component but should not be interpreted as establishing clinical efficacy of all A09AC01 formulations.

Pharmacokinetic considerations

Conventional pharmacokinetic concepts have limited applicability to the pepsin component. Pepsin is a large protein enzyme, with human pepsin having a molecular mass of approximately 34 kDa, and its intended action occurs within the gastrointestinal lumen. Systemically relevant absorption of intact orally administered pepsin would not ordinarily be expected; like other dietary or therapeutic proteins delivered to the gastrointestinal tract, it is subject to digestion and degradation. Consequently, plasma concentration, volume of distribution, plasma half-life and conventional systemic clearance parameters are not clinically meaningful descriptors of its intended therapeutic action.

Acidifying salts require separate consideration. Betaine hydrochloride dissociates in aqueous gastric fluid, supplying protons and chloride together with betaine. Thus, although its acidifying action is local and transient, the resulting betaine belongs to normal human intermediary metabolism and can be systemically absorbed. Betaine functions physiologically as an organic osmolyte and methyl donor, particularly in one-carbon metabolism.

This distinction between the enzyme and acidifying components is important for lactation assessment: the combination acts primarily in the maternal gastrointestinal tract, but not every constituent necessarily remains confined to it.

2. Toxicological Profile

Therapeutic exposure

At therapeutic oral exposure, the principal toxicological considerations for A09AC01 preparations are expected to arise from local gastrointestinal effects of excessive acidification, product-specific excipients, and hypersensitivity to enzyme proteins rather than from systemic pepsin toxicity.

Betaine hydrochloride can substantially reduce gastric pH. Controlled studies have administered single oral doses ranging from approximately 1.5 to 4.5 g while examining gastric re-acidification, demonstrating a clear pharmacodynamic effect on gastric acidity. In susceptible individuals, excessive acidification could therefore theoretically aggravate acid-related upper gastrointestinal symptoms or pre-existing mucosal disease.

The toxicological significance of concentrated acidifying chemicals should not be directly extrapolated to appropriately formulated medicinal preparations. Nevertheless, inappropriate dosing or use in the presence of significant gastric or duodenal mucosal disease may increase the likelihood of local irritation.

Pepsin and hypersensitivity

Pepsin is not generally associated with systemic toxicity after conventional oral exposure. A more clearly documented toxicological property of enzyme proteins is their allergenic potential following occupational inhalational exposure.

IgE-mediated occupational asthma attributable to pepsin has been documented, including positive skin testing, specific IgE and positive inhalation challenge. Occupational rhinoconjunctivitis and other respiratory sensitization phenomena have also been reported. Reviews of occupational exposure to pepsin and related enzymes likewise support the capacity of enzyme dust to cause airway sensitization.

These findings concern repeated inhalational exposure to enzyme dust and should not be interpreted as demonstrating comparable risk from correctly administered oral medicinal preparations. EFSA evaluations of pepsin-containing food enzymes similarly recognize occupational respiratory sensitization while considering allergic reactions after dietary exposure to be unlikely, although they cannot be completely excluded.

Acute overdose

There is no well-defined class-specific systemic poisoning syndrome for therapeutic pepsin/acid combinations. Excessive ingestion would be expected principally to increase the risk of gastrointestinal irritation, epigastric discomfort, nausea, or acid-related symptoms, depending strongly on the acidifying substance, concentration and formulation.

No specific antidote exists for the class. Management of clinically significant overdose is therefore principally supportive and should be directed by the actual formulation and clinical manifestations rather than by the ATC classification alone.

No convincing evidence identifies therapeutic pepsin/acid preparations as a clinically important source of cumulative organ toxicity, genotoxicity or carcinogenicity. However, absence of such reports should not be interpreted as evidence derived from systematic long-term safety studies of all products within the class.

3. Lactation Pharmacology and Breast-Milk Exposure

Direct lactation evidence

No adequate published human lactation studies specifically evaluating therapeutic A09AC01 pepsin-and-acid combination preparations were identified.

In particular, adequate data describing maternal administration followed by serial measurement of the medicinal components in human milk, calculation of a milk-to-plasma ratio, determination of infant plasma concentrations, or prospective assessment of exposed breastfed infants are lacking.

Accordingly:

Milk-to-plasma ratio: not established for A09AC01 preparations.
Relative infant dose (RID): not established.
Infant plasma concentrations: not established.

An RID should not be inferred in the absence of suitable maternal dosing and milk-concentration data.

Pepsin

Clinically meaningful transfer of orally administered intact pepsin into human milk is mechanistically unlikely.

Pepsin is a large protein enzyme whose therapeutic site of action is the gastric lumen. Significant absorption of pharmacologically active intact pepsin into the maternal systemic circulation is not expected. Without appreciable maternal plasma exposure, subsequent transfer of intact exogenous pepsin into mammary secretions would also be expected to be negligible.

Even if trace quantities of enzyme-derived peptides reached milk, oral exposure of the infant would occur through the gastrointestinal tract, where proteins and peptides undergo further digestion. Thus, systemic pharmacological exposure of the breastfed infant to active maternal pepsin appears biologically implausible under ordinary therapeutic conditions.

This conclusion is mechanistic, not the result of controlled milk-transfer studies.

Acidifying components and betaine

Acidifying components require a different interpretation because small molecules generated after dissociation may enter normal systemic metabolic pools.

For betaine-hydrochloride-containing preparations, hydrochloride-mediated gastric acidification itself does not constitute a substance that could be meaningfully “transferred” into milk as gastric acidity. Betaine, however, is systemically relevant and is also a normal constituent of human milk.

Human studies have directly demonstrated endogenous betaine in breast milk. Concentrations vary considerably between studies and populations. For example, one controlled nutritional study reported mean milk betaine concentrations of approximately 7.0 nmol/mL in a placebo group and 12.3 nmol/mL in women receiving supplemental choline; broader metabolomic studies have likewise demonstrated naturally occurring betaine in human milk with substantial interindividual and geographical variability. Another study specifically detected betaine in breast-milk samples from lactating women.

These observations are important physiologically but do not establish the milk exposure produced by maternal therapeutic betaine hydrochloride. Endogenous milk concentrations cannot be used to calculate an RID for an A09AC01 medicine.

Available data therefore support two separate conclusions:

1. betaine is physiologically present in human milk; and
2. the incremental milk concentration attributable specifically to maternal therapeutic use of a pepsin/betaine-hydrochloride preparation has not been adequately characterized.

This distinction prevents normal physiological exposure from being incorrectly presented as direct evidence of drug safety.

Expected infant exposure

For the pepsin component, systemic infant exposure is expected to be negligible on mechanistic grounds.

For betaine or other absorbable acidifying constituents, some maternal systemic exposure and subsequent contribution to milk composition may be biologically possible. However, the magnitude of additional infant exposure following therapeutic A09AC01 dosing is unknown.

The overall class therefore has a pharmacological profile suggesting low potential for clinically significant exposure of the breastfed infant, but the strength of this conclusion is limited by the absence of direct studies of the medicinal combinations.

4. Effects in the Breastfed Infant and Effects on Lactation

Clinical effects in breastfed infants

No adequate published case series, prospective cohorts or controlled studies documenting adverse effects specifically in infants breastfed during maternal treatment with A09AC01 preparations were identified.

Equally, the absence of identified reports should not be interpreted as proof that adverse effects cannot occur. The direct clinical evidence base is simply sparse.

From a mechanistic perspective, pharmacologically significant exposure to intact pepsin is unlikely. Potential infant effects related to an absorbable acidifying component would depend upon the actual substance, maternal dose, maternal systemic exposure and resulting milk concentration.

Particular caution in interpretation is appropriate for premature neonates and medically fragile infants because neonatal metabolic and renal handling may differ substantially from that of older healthy infants. Nevertheless, there is currently no evidence establishing a specific neonatal toxicity syndrome from maternal therapeutic use of this ATC class.

Effects on milk production

No adequate evidence was identified showing that pepsin and acid preparations directly suppress prolactin secretion, interfere with oxytocin-mediated milk ejection, delay lactogenesis or reduce established milk production.

A direct pharmacological effect on lactation is also not predicted from the principal mechanism of action, which is gastrointestinal.

Severe maternal gastrointestinal intolerance, reduced oral intake or other clinically significant adverse effects could theoretically influence lactation indirectly, but this would represent a consequence of maternal illness or intolerance rather than a demonstrated lactation-specific pharmacological effect.

5. Lactological Safety Assessment and Clinical Recommendations

The lactation assessment of A09AC01 rests predominantly on pharmacological and mechanistic evidence rather than direct breastfeeding studies.

For pepsin, the large molecular size, gastrointestinal site of action and expected lack of clinically significant systemic absorption make meaningful transfer of active enzyme into breast milk unlikely. For acidifying components such as betaine hydrochloride, the local gastric effect must be distinguished from subsequent systemic handling of betaine. Betaine is naturally present in human milk, but therapeutic milk-transfer data for betaine hydrochloride in A09AC01 combinations are insufficient to quantify additional infant exposure.

Breastfeeding compatibility

Available evidence does not provide a pharmacological basis for routine interruption of breastfeeding solely because a mother requires a conventional therapeutic pepsin-and-acid preparation.

However, this conclusion is based primarily on low expected exposure and physiological reasoning rather than robust direct clinical lactation studies. It should therefore be expressed as probable compatibility under therapeutic conditions, rather than as demonstrated safety.

The exact formulation remains important. A favourable assessment of pepsin cannot automatically be extrapolated to every additional active ingredient contained in a combination product. Each formulation should be reviewed for other pharmacologically active components.

Some currently marketed betaine-hydrochloride-containing products accordingly advise breastfeeding women to consult a healthcare professional before use, reflecting the limited direct evidence rather than documentation of a specific lactational toxicity.

Infant monitoring

Routine laboratory monitoring of a healthy, term breastfed infant is not pharmacologically justified solely because of maternal therapeutic use of a simple pepsin/acid preparation.

Ordinary clinical observation is sufficient in most circumstances. If maternal doses are unusually high, the preparation contains additional active ingredients, or the infant is premature or medically fragile, individualized assessment is appropriate.

Dose–feed timing

Separating maternal administration from breastfeeding is unlikely to provide a meaningful reduction in infant exposure to the pepsin component because appreciable systemic maternal exposure is not expected.

For betaine-containing preparations, there are insufficient milk pharmacokinetic data to define an evidence-based optimal interval between dosing and breastfeeding. Routine dose–feed scheduling therefore cannot be recommended.

Pumping and discarding milk

There is no evidence-based indication for routine pumping and discarding of breast milk (“pump and dump”) during conventional maternal treatment with a simple A09AC01 preparation.

Temporary interruption would require a separate clinical justification, such as significant maternal poisoning, exposure to another hazardous component of a combination product, or another circumstance unrelated to ordinary therapeutic pepsin/acid use.

Overall lactological assessment

6. Conclusion

A09AC01 comprises pepsin and acid preparations, a group of digestive combinations whose pharmacological action is predominantly local within the maternal gastrointestinal tract. WHO currently assigns no DDD to A09AC01.

Direct lactation evidence for the class is poor. No adequate studies were identified that permit calculation of a milk-to-plasma ratio or relative infant dose, and infant plasma exposure has not been characterized. Consequently, numerical milk-exposure estimates should not be inferred.

The pharmacological characteristics of pepsin are reassuring: it is a large proteolytic enzyme acting within the gastric lumen, and clinically important maternal systemic absorption—and therefore transfer of active exogenous enzyme into breast milk—is mechanistically unlikely.

Acidifying components must be assessed separately. Betaine hydrochloride dissociates and transiently increases gastric acidity, while betaine enters normal physiological metabolism. Betaine is naturally measurable in human milk, but available physiological milk measurements cannot be used as surrogate pharmacokinetic data for maternal A09AC01 therapy.

The principal toxicological concerns at therapeutic use are local gastrointestinal intolerance from excessive acidification and, for enzyme proteins, allergenic sensitization principally documented in occupational inhalational settings rather than after medicinal oral exposure. No class-specific toxicity in breastfed infants has been established.

On balance, conventional therapeutic use of a simple pepsin-and-acid preparation is unlikely to produce clinically significant exposure of a breastfed infant, and breastfeeding would not ordinarily require interruption. This assessment is predominantly mechanistic rather than supported by dedicated clinical lactation studies. Additional caution is appropriate when the formulation contains other active ingredients, maternal exposure is excessive, or the breastfed infant is premature, neonatal or medically fragile.

Selected References

1. WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index: A09AC01 — Pepsin and acid preparations. Current ATC classification.
2. WHO Collaborating Centre for Drug Statistics Methodology. Guidelines for ATC classification and DDD assignment. Digestives, including enzymes.
3. Yago MR, Frymoyer AR, Smelick GS, et al. Gastric re-acidification with betaine HCl in healthy volunteers with rabeprazole-induced hypochlorhydria. Molecular Pharmaceutics. 2013;10:4032–4037.
4. Yago MR, Frymoyer A, Benet LZ, et al. The use of betaine HCl to enhance dasatinib absorption in healthy volunteers with rabeprazole-induced hypochlorhydria. AAPS Journal. 2014;16:1358–1365.
5. Surofchy DD, Frassetto LA, Benet LZ. Food, acid supplementation and drug absorption—a complicated gastric mix: a randomized control trial. Pharmaceutical Research. 2019.
6. Craig SAS. Betaine in human nutrition. American Journal of Clinical Nutrition. 2004;80:539–549.
7. Cartier A, Malo JL, Pineau L, Dolovich J. Occupational asthma due to pepsin. Journal of Allergy and Clinical Immunology. 1984;73:574–577.
8. van Kampen V, Lessmann H, Brüning T, Merget R. Occupational allergies against pepsin, chymosin and microbial rennet. Pneumologie. 2013;67:260–264.
9. EFSA Panel on Food Contact Materials, Enzymes and Processing Aids. Safety evaluation of food enzyme rennet containing chymosin and pepsin A from calf abomasum. EFSA Journal.