The IntoMed® tools designed in this study provide, in a fast and accessible way, reliable information about the tolerability of different drugs according to their excipient content in patients with HFI and other related intolerances. Despite the progress in drug labelling, questions related to drug and sweetener tolerance (which in many cases are also excipients) are still frequent in HFI patients and their families [34].

European medicine legislation contraindicates fructose, sucrose, invert sugar, sorbitol, maltitol, lactitol and isomaltitol because they can have serious or even fatal consequences if they are administered to HFI patients. In the last legislation update [6], it was established that a warning for oral or parenteral (not intravenous) products with fructose and sorbitol at dosages of less than 5 mg/kg/day did not need to be included. This means that an oral drug with less than 5 mg/kg/day of fructose or sorbitol will not have a warning, while a drug with the same amount of contraindicated polyalcohols will, which is inconsistent considering polyalcohol metabolism. Polyalcohols undergo incomplete hydrolysis by disaccharidases in the gastrointestinal tract; for example, partial hydrolysis occurs in approximately 40% of maltitol (and sorbitol is partially absorbed), approximately 10% of isomaltitol and approximately 2% of lactitol [5, 23]. Although these polyalcohols are not permitted in HFI patients, the total absorbed fructose (sorbitol) would be less than the amount of fructose that is currently allowed by the legislation. The Italian Health Institute has been more restrictive, and it has established a fructose or sorbitol threshold of 2.4 mg/kg/dose for parenteral products and vaccines in HFI patients [35]. For this reason, the apps include any difference in the classifications of parenteral non-IV and IV drugs, as well as to simplify searches for users. Mannitol is not considered a contraindicated polyalcohol in the legislation; however, it has been classified as not recommended in this review. This decision is derived from its unknown metabolism. Mannitol, a fructose polyalcohol, is metabolised in the liver at approximately 7–10% and can be transformed into fructose or into CO2 by an unknown metabolic pathway [23, 24]. In 10% or 20% intravenous mannitol solutions, the amount provided is very high, 50–100 g/500 ml, respectively, and the consequences of its administration are unknown, which is the reason for its not recommended classification.

On the other hand, intravenous sucrose is not contraindicated because after its administration, the blood glucose concentration does not increase, and it is mainly excreted in the urine as a disaccharide [26] (because there is no disaccharidase activity outside the gut). The absence of this enzymatic activity outside the gut explains why there is no warning for parenteral sucrose formulations in the current legislation, but there are doubts about its tolerability among some health care professionals [35,36,37].

Glucose has always been the recommended sweetener in HFI patients. However, a recent study in aldolase B knockout mice has demonstrated that high glucose consumption in these mice can activate the polyol pathway and produce fructose from glucose (glucose to sorbitol by aldolase reductase, and sorbitol to fructose by sorbitol dehydrogenase), resulting in liver alterations and growth delay [21]. Further studies in humans with HFI are needed to understand the implications and consequences of fructose consumption, establishing recommended limits and/or contraindications. For this reason, glucose and its derivatives have been designated as “suitable with considerations”, but these recommendations will be updated as more evidence becomes available.

Serious errors in some sweetener definitions have been found in technical data sheets, especially in glucose derivatives. Hydrogenated starches (a synonym for polyalcohols) are obtained by a partial transformation of glucose into sorbitol, and there has been confusion between starch (suitable) and hydrogenated starch (contraindicated). On the other hand, pregelatinised or modified starch has been confused with hydrogenated starch, but in modified starch, part of its glucose chains are broken to obtain variations in its viscosity without fructose or sorbitol content. Additionally, corn syrup should be a synonym of glucose syrup, but sometimes, to increase the sweetening power of corn syrup, part of the starch or glucose is isomerised to fructose by glucose isomerase, obtaining HFCS (glucose-fructose syrup). Some confusion might appear around the term corn syrup because it has been incorrectly used to refer to both glucose syrup and HFCS [33]. Differences between food and drug legislation in relation to glucose and fructose syrup have been found. Food legislation defines glucose syrup as glucose products with up to 5% fructose, calling them “glucose and fructose syrup” only when the fructose is greater than 5% [38]. However, drug legislation states that if the glucose syrup contains fructose, it should be indicated in the ingredient list [6], but this has not always been done.

Gums and colloidal polysaccharides were classified as suitable (with considerations) in the apps in HFI patients, although some controversy has been found concerning their composition. Gums and other colloidal polysaccharides (carrageenan type) are not hydrolysed at the gastrointestinal level, and their absorption will be minimal. However, some of them may include sugars to improve their quality, or they may have been obtained through glucose or sucrose fermentation. For this reason, it is necessary to be cautious until more information is provided [19, 20, 22, 27, 28].

In current medicine legislation, aromas and flavours can be declared in generic terms, although components with a recognised action or effect must be specifically declared [6]. Supplements are added to flavours to facilitate storage, standardisation, dilution, dissolution and/or stabilisation, and they may be sugars or polyalcohols that are contraindicated in HFI (sorbitol, isomaltitol, maltitol or lactitol) [39]. Furthermore, there are flavours that contain fructose, sucrose or sorbitol, and according to HFI dietary guidelines, they are not recommended (e.g., honey flavouring, vanillin, vanilla flavouring, liquorice extract, etc.) [4]. Even so, there are fruit juices or extracts with unknown compositions, colours obtained by mechanical methods from fruit (beet red) or sugar derivatives (caramel colour). In these cases, there is no warning for HFI patients on the labels.

Sucrose esters or sorbitol esters (spans) obtained by the partial esterification of sorbitol with fatty acids are hydrolysed by esterases and release sucrose or sorbitol [30,31,32]. Spans are usually present in topical preparations and in this case are considered suitable [40, 41], but when they are used in oral or parenteral drugs, caution is needed in HFI patients. In contrast, polysorbates (tweens) are sorbitol esters with polyoxyethylene fatty acids, but the link between sorbitol and ethylene oxide cannot be hydrolysed [30]. Despite this, polysorbate intoxication after the administration of an intravenous drug with polysorbate 80 was described in an HFI patient with hepatorenal alterations and hypoglycaemia, similar to fructose intoxication [42]. There are also studies describing liver and kidney toxicity in non-HFI patients taking drugs containing polysorbates [43], so it is possible that the alterations were caused by the toxicity of polysorbate itself rather than fructose intoxication.

There is increasing interest in electronic health (eHealth), especially in mobile technology (mHealth), in recent years, with the aim of helping patients, consumers and even health professionals. These technologies could be useful due to the lack of information on rare diseases [7, 44] and because many health professionals encounter few patients with these characteristics throughout their professional career, and therefore, they require the help of decision-making tools. These apps contain information not only about excipients with box warnings but also about some other sugars, sweeteners or excipients for which there is currently no specified legislation for HFI patients but that may produce intolerance when they are present in drugs. In addition, the possibility of selecting other diseases was included in the development of the apps, as HFI has also been linked with other pathologies, such as type 2 diabetes mellitus or glucose intolerance [8, 9] and celiac disease [10]. The usability of digital applications by potential users is a key parameter of good practice in their development. In our case, the reliability and usability of the tools were demonstrated, although the score was better in patients than in health professionals, possibly due to the problems they encountered daily. Furthermore, the sample used for this study consisted of a multidisciplinary team (included in the design), HFI patients and their families, and health professionals. The SUS is a frequently used questionnaire in eHealth and mHealth because it is an easy and quick tool [45] and is validated in Spanish [15], although it was not designed to evaluate the usability of mHealth apps.

The present study has several limitations. The information about excipient metabolism described in the literature is old and incomplete, and it is not specific for HFI patients. For this reason, in some cases, it is not possible to obtain conclusions about metabolism or composition related to fructose. Moreover, the information for classifying excipients in these apps depends on updates from the Spanish Medicine Agency, so a warning is included for users.

In conclusion, IntoMed® is a new tool for finding information about the tolerability of drugs containing excipients in patients with HFI and other related intolerances. It is a fast and reliable system that covers the current excipient legislation and expands it with other specific information. It is important to highlight that there are excipients not included in the legislation and do not appear on labels; however, due to their metabolic involvement, they should have a warning for HFI patients. These excipients include mannitol (especially in IV drugs), fruit syrups, honey, sulfite caramel and vanilla. Moreover, it is necessary to take special precautions with glucose and glucose syrups because of frequent and important errors in compounding and their potential endogenous production of fructose. Through the review carried out in this study, the deficiencies of some excipients with unclear information have been revealed. Furthermore, it has been possible to respond to these unmet needs.