Paediatric excipient risk assessment (PERA) tool and application for selecting appropriate excipients for paediatric dosage forms - Part 2.

It is necessary to use a scientifically sound process for excipient risk evaluation, selection, and management in order to develop paediatric medicinal products that are both safe and effective. The "Paediatric Excipient Risk Assessment (PERA)" framework, which proposes a comprehensive approach by considering all relevant factors related to patient, dosage form, and excipient attributes, was developed and published as part 1 of this paper series, to enable the rational selection of excipients for paediatric medicinal products. This article is Part 2 of the series and presents the PERA tool that allows easy adoption of the PERA framework. Using a straightforward heat map scoring approach (Red, Yellow, and Green category) for risk evaluation, the PERA tool can be used to compare and choose excipients. The PERA tool will help users identify potential gaps in excipients information that will help with risk-based mitigation planning. Several case studies covering frequently used and novel excipients for oral, as well as the choice of excipient for parenteral products for neonatal administration, serve to illustrate the PERA tool's usefulness.

Selecting appropriate excipients for paediatric dosage form - Paediatric excipients risk assessment (PERA) framework - Part 1.

Excipients are often the major component of the formulation that critically affect the dosage form, manufacturing process, product performance, stability and safety. They exert different roles and functions in a dosage form. Selecting excipients with appropriate safety and tolerability is a major hurdle in paediatric formulation development. The suitability of a particular excipient will be dependent on the context of its use with regard to the paediatric age range, acute versus chronic use, and clinical risk-benefit of the disease, active and excipient. Scientists are encouraged to apply the principle of risk-benefit to assess the suitability of excipients to the specific paediatric population. Indicative list of parameters that should be taken into consideration and hierarchy of information sources when assessing the excipients risks is provided by regulatory agencies. However, the approach to be taken and details of how the risk evaluation should be undertaken are lacking. There is a need for a systematic approach to selection of excipients and assessment of the risk of excipient exposure. The Paediatric Excipients Risk Assessment (PERA) framework developed and proposed in this paper provides a structured, systematic decision-making framework via customizable tools and processes that can help to improve the transparency and communications on the selection and justification of use of excipients in a paediatric formulation.

Risks of dairy derived excipients in medications for lactose intolerant and cow milk protein allergic patients.

The use of lactose and cow milk protein (CMP) as potential allergens in pharmaceuticals and their ability to cause allergic reactions remains a significant concern in medicine. Lactose, a common pharmaceutical excipient due to its inert, inexpensive, and stable properties, is found in many prescription-only and over-the-counter medications. However, despite their widespread use, individuals with lactose intolerance (LI) or cow milk protein allergy (CMPA) may experience adverse reactions to these excipients. This study investigated the prevalence of lactose and other dairy-derived ingredients in pharmaceuticals marketed in Portugal. Using the Summary of Product Characteristics (SmPC) from the INFOMED database, various medications, including analgesics, antipyretics, non-steroidal anti-inflammatory drugs (NSAIDs), and antiasthmatics, were analyzed. Results showed a high prevalence of dairy-derived excipients, particularly in antiasthmatic drugs (62.6%) and NSAIDs (39%). Although CMP are not explicitly mentioned in SmPCs, the presence of lactose as an ingredient poses a risk of cross-contamination. The findings emphasize the need for healthcare professionals to be aware of potential allergens in medications and the importance of developing lactose-free alternatives to ensure the safety of patients with LI and CMPA. Further research is required to assess the safety and implications of lactose in medicines for these populations.

Alpha-gal syndrome: when treatment of hypovolemic shock can lead to anaphylaxis.

Delayed anaphylaxis after ingestion of red meat because of galactose-alpha-1,3-galactose (alpha-gal) syndrome has increased in recent years. The mechanism involves an immunoglobulin E reaction to alpha-gal, a molecule found in mammalian meat, dairy products, medications and excipients containing mammalian-derived components, and tick salivary glycans. Sensitization occurs due to the bite of a lone star tick and the transmission of alpha-gal molecules into person's bloodstream. We describe a case of alpha-gal syndrome with severe food, drug, and perioperative allergy in which anaphylaxis with hypovolemic shock occurred immediately after an emergency surgical procedure, when a gelatin-containing drug was injected. This case study confirms that the clinical manifestations of alpha-gal syndrome could be different depending on the route of administration, with immediate reactions if an alpha-gal-containing drug is injected and delayed type allergic manifestations occurring several hours after oral intake. The purpose of this report is to highlight the importance of risk communication in case of exposure to medical products and surgical procedures of patients with alpha-gal syndrome and to encourage drug manufacturers to indicate clearly the origin of excipients in product literature.

Commentary: Is Polyethylene Glycol Toxicity From Intravenous Methocarbamol Fact or Fiction?

Methocarbamol is an antispasmodic muscle relaxant and was the fourth most-prescribed muscle relaxant by volume in the United States in 2021. Intravenous (IV) methocarbamol contains the excipient, polyethylene glycol (PEG), which has been implicated in metabolic acidosis and nephrotoxicity. Intravenous methocarbamol was first approved by the US Food and Drug Administration in 1959 and at that time the IV methocarbamol prescribing information warned of PEG-associated adverse drug events in patients living with renal impairment; however, the manufacturer acknowledged data were lacking to objectively support this claim. Clinicians prescribing and dispensing IV methocarbamol may encounter the warning for PEG-associated metabolic acidosis and nephrotoxicity without knowing the potential risks, or lack thereof, supporting or disavowing this phenomenon. This commentary debates the merits supporting and arguments refuting PEG-associated metabolic acidosis and nephrotoxicity in patients treated with IV methocarbamol.

Inconsistent excipient listings in DailyMed: implications for drug safety.

Excipients, or inactive ingredients, are a frequent cause of medication intolerance and allergy. Patients and clinicians concerned about medication allergies and sensitivities rely on the U.S. National Library of Medicine's DailyMed for accurate lists of excipients. Based on our anecdotal discovery of several examples of excipient omissions, we wished to examine the accuracy of DailyMed's listings more systematically in a sample of commonly prescribed medications. The objective of the study is to identify the frequency of inconsistency of excipient reporting within the DailyMed website. We performed a database audit of the Structured Product Labeling XML file provided by the drug manufacturer to the Food and Drug Administration and DailyMed for two randomly selected formulations of each of 50 commonly prescribed medications. For each of the 100 formulations, we compared the excipients listed in the "Description" to those in the "Ingredients and Appearance" sections in DailyMed. The Structured Product Labeling data file provided by the drug manufacturer contained internal inconsistencies of excipients in 39% of the formulations examined. Despite the use of Structured Product Labeling, the drug manufacturer's medication labels provided to the FDA and reported by DailyMed often contain conflicting information about inactive ingredients. Patients with allergies and excipient sensitivity should be aware of these discrepancies and consult multiple sections of the label to identify potential allergy-inducing inactive ingredients.

How Should Regulators and Manufacturers Prevent Avoidable Deaths of Children From Contaminated Cough Syrup?

This commentary responds to a case about diethylene glycol-contaminated glycerin in cough syrup. Glycerin is a commonly used excipient in medicines to improve texture and taste. Excipients are typically pharmacologically inactive ingredients contained in prescription and over-the-counter drugs that play a critical role in the delivery, effectiveness, and stability of active drug substances. The commentary first canvasses how contaminants enter the excipient supply chains. One way is by misleading labeling or intentional adulteration by manufacturers or suppliers. Another way is by human or systemic error. This commentary then discusses quality control testing and suggests the ethical and clinical importance of increased transparency in excipient supply chains.

Severe cutaneous adverse reaction to drug excipient following brand-to-generic switch of levetiracetam.

PURPOSE: Levetiracetam is an antiepileptic drug known for its high tolerability, and severe adverse drug reactions are rare. We report the case of a severe cutaneous adverse drug reaction in a patient who was switched from brand-name to generic levetiracetam. SUMMARY: A 29-year-old woman undergoing contrast-enhanced computed tomography developed lesions over her trunk starting 6 hours after imaging. Although initially diagnosed as an allergy to the radiocontrast agent, the condition progressively worsened into toxic epidermal necrolysis-drug reaction with eosinophilia and systemic symptoms overlap syndrome, despite adequate hydration and treatment. Investigation of the patient's medications revealed that she had been switched from brand-name to generic levetiracetam a week before the onset of symptoms. Levetiracetam was immediately discontinued, with the patient recovering after 2 weeks of intensive care. Adverse drug reaction analysis identified excipients in generic levetiracetam as the likely cause of the severe reaction. CONCLUSION: This is the first reported case of severe cutaneous drug allergy after a brand-to-generic switch for levetiracetam. Brand-to-generic switches of medications can potentially cause severe allergic reactions due to differences in excipients.

Quantitative Investigation on Exposure to Potentially Harmful Excipients by Injection Drug Administration in Children Under 2 Years of Age and Analysis of Association with Adverse Events: A Single-Center, Retrospective Observational Study.

INTRODUCTION: Potentially harmful excipients (PHEs) for children have been reported and the need for information collection has been advocated. However, studies on the actual occurrence of adverse events are limited. This study investigated the quantitative exposure of PHEs via injection and their association with adverse events in children under 2 years of age. MATERIALS AND METHODS: As a single-center observational study, children aged 0-23 months received injectable drugs from April 1, 2018, to March 31, 2023 were included. Information on PHE exposure and adverse events after administration were extracted from medical records. Sodium benzoate, benzyl alcohol, ethanol, glycerol, lactose, polyethylene glycol paraben, polysorbate, propylene glycol, sorbitol, sucrose, sulfite, and thimerosal were selected as PHEs. RESULTS AND DISCUSSION: 6265 cases, 333,694 prescriptions, and 368 drugs (264 ingredients) were analyzed. The median age was 0.63 years (interquartile range [IQR] 0.1-1.1). 72,133 prescriptions, 132 drugs and 99 ingredients contained PHE; 2,961 cases exposed to PHE and 1825 cases exceeding permitted daily exposure. The drug with the highest number of exposure cases was hydroxyzine, and the highest number of prescriptions was heparin (both drugs contain benzyl alcohol). In association between adverse events and PHE exposure, higher doses in cases of adverse event occurrence were found in benzyl alcohol, glycerol, polyethylene glycol, and polysorbate exposed cases. Among thimerosal-exposed cases, "developmental delay" was more frequent in exposed cases, but the causal relationship was unknown. Further investigation is needed to clarify the relationship between adverse events and PHE exposure. Additionally, more precise information on PDE for pediatrics including neonates is necessary.

Bridging the Gap: A Comparative Investigation of Pharmaceutical Excipient Regulations.

Since the awareness of adverse effects associated with pharmaceutical excipients in drug formulations, these excipients are no longer considered inert substances. Numerous countries have recognized the potential risks that they pose to patients and have implemented diverse regulations to evaluate their safety, compatibility, toxicity, and quality. Regulatory authorities have proactively implemented measures to evaluate excipients and have formulated comprehensive guidelines that manufacturers are obligated to follow. This review primarily highlights the different provisions governing the utilization of excipients in drug formulation by regulatory authorities worldwide. Nonetheless, it is worth noting that there are still many countries that do not perceive excipients as posing a potential threat.

The role of skin tests with polyethylene glycol and polysorbate 80 in the vaccination campaign for COVID-19: results from an Italian multicenter survey.

Summary: Background. International guidelines suggested skin tests with Polyethylene-glycol (PEG) and polysorbate 80 (PS-80), to investigate a possible hypersensitivity to these excipients either to identify subjects at risk of developing allergic reactions to Covid-19 vaccines, or in patients with suspected IgE mediated hypersensitivity reactions (HR) to the Covid-19 vaccine. The main purpose of this study was to investigate the prevalence of PEG and PS sensitization in patients with a clinical history of HR to drugs containing PEG/PS and in patients with a suspected Covid-19 vaccine immediate HR. Methods. This was a multicenter retrospective study conducted by allergists belonging to 20 Italian medical centers. Skin testing was performed in 531 patients with either a clinical history of suspected hypersensitivity reaction (HR) to drugs containing PEG and/or PS-80 (group 1:362 patient) or a suspected HR to Covid-19 vaccines (group 2: 169 patient), as suggested by the AAIITO/SIAAIC guidelines for the "management of patients at risk of allergic reactions to Covid-19 vaccines" [1]. Results. 10/362 (0.02%) had positive skin test to one or both excipients in group 1, 12/169 (7.1%) in group 2 (p less than 0.01). In group 2 HRs to Covid-19 vaccines were immediate in 10/12 of cases and anaphylaxis occurred in 4/12 of patients. Conclusions. The positivity of skin test with PEG and or PS before vaccination is extremely rare and mostly replaceable by an accurate clinical history. Sensitization to PEG and PS has to be investigated in patients with a previous immediate HR to a Covid-19 vaccine, in particular in patients with anaphylaxis.

Cutaneous anaphylactoid reaction to polyoxyethylene hydrogenated castor oil in dogs.

BACKGROUND: Polyoxyethylene hydrogenated castor oil (HCO ethoxylates) is a nonionic surfactant used as an excipient for ointments and injections in human and veterinary drugs. Several polyethylene glycol (PEG) derivatives can be obtained depending on the number of moles of ethylene oxide (EO). HCO ethoxylates have the potential to cause anaphylactoid reactions. There is little published information about these types of reactions in dogs. OBJECTIVE: To determine the potential for HCO-ethoxylate-containing drugs to cause anaphylactoid reactions in dogs, employing intradermal testing (IDT) with various concentrations of HCO ethoxylates (HCO-25, -40, -60 and -80). ANIMALS: Four healthy male laboratory dogs. MATERIALS AND METHODS: We performed IDT with drugs containing HCO ethoxylates and HCO ethoxylates alone to determine threshold concentrations. The IDT scores and threshold concentrations were compared. Analysis of skin biopsies from IDT sites was used to measure the percentage of degranulated mast cells. The effect of histamine at IDT sites was investigated by pre-treatment with an antihistamine. RESULTS: All HCO-ethoxylate-containing drugs caused a wheal-and-flare reaction. The threshold concentrations (0.001% and 0.00001%) of each HCO-ethoxylate depended on the number of moles of EO (p < 0.05). Mast cell degranulation was enhanced by all HCO ethoxylates. The HCO-60-induced reaction was suppressed by an oral antihistamine. CONCLUSIONS AND CLINICAL RELEVANCE: The threshold concentration can serve as a consideration for developing safe new drug formulations and for clinical decision-making around using drugs containing PEG derivatives. IDT is useful to predict the risk of adverse effects. Antihistamines could demonstrate a prophylactic effect.

Excipients and Adverse Events.

Pharmaceutical excipients are substances formulated with an active ingredient in a medication. This article has provided a brief discussion on excipients, the purpose of excipients, the selection of appropriate excipients, the use of excipients in formulation development by compounding pharmacists/manufacturers, excipient examples and usage, the numerous incompatibilities that should be considered when choosing an excipient, and a list of adverse effects related to excipients.

Hypersensitivity reactions to anti-SARS-CoV-2 vaccines: Basophil reactivity to excipients.

Basophil activation test (BAT) can tackle multiple mechanisms underlying acute and delayed hypersensitivity to drugs and vaccines and might complement conventional allergy diagnostics but its role in anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-related hypersensitivity is ill-defined. Therefore, 89 patients with possible hypersensitivity (56 % with delayed mucocutaneous manifestations) to anti-SARS-CoV-2 vaccines were tested with BAT for Macrogol 3350, DMG-PEG 2000, PEG 20000, polysorbate-80 and trometamol and compared to 156 subjects undergoing pre-vaccine BAT. A positive BAT was associated with delayed reaction onset (p = 0.010) and resolution (p = 0.011). BAT was more frequently positive to DMG-PEG 2000 than to other excipients in both groups (p < 0.001). DMG-PEG 2000 reactivity was less frequent in vaccine-naïve (6 %) than vaccinated subjects (35 %, p < 0.001) and associated with mRNA-1273 vaccination. DMG-PEG 2000 BAT might therefore have a diagnostic role in subjects with delayed hypersensitivity reactions. Natural immunity might be a key player in basophil activation.