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.

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.

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.

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.

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.

The Evaluation of pediatric patients with suspected polyethylene glycol and polysorbate allergy before mRNA SARS-CoV2 vaccination

mRNA vaccines, particularly, have been associated with an increased risk of allergic reactions and rarely anaphylaxis. Although rare, vaccine reactions can cause significant anxiety and fear in the population, leading to indecision and vaccine refusal. This study aimed to retrospectively evaluate the role of polyethylene glycol (PEG) sensitivity in vaccination decision-making in pediatric patients at high risk of allergy or with suspected allergic reactions to the first dose of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccine. Seventeen enrolled patients were found to have decreased readiness to receive the Coronavirus Disease 2019 (COVID-19) vaccine after developing hypersensitivity to multiple and/or injectable drugs. Skin testing was performed. A basophil activation test with PEG-2000 and 4000 was performed on three patients who were ineligible for skin prick tests. Nine patients with negative tests received the vaccine without complications. One patient had urticarial angioedema despite negative tests. Three patients with positive tests did not agree to desensitization with the mRNA vaccine, and one of them was vaccinated with the inactivated COVID-19 vaccine. Four patients recurred despite negative tests. The general recommendation for patients describing severe reactions to drugs, foods, and allergens, such as toxins that do not contain the adjuvants of the SARS-CoV-2 vaccines, is to be routinely vaccinated with safety precautions. Excipients such as PEG and polysorbate-80 used in COVID-19 vaccines could be potential allergens, but this hypothesis is unclear. The predictive values of these adjuvants for skin testing and in vitro testing are controversial. Further research is needed on the hypersensitivity reactions of adjuvants, the predictive values of skin tests, and etiopathogenesis (AU)

Two cases of drug induced hypersensitivity to dolutegravir-rilpivirine fixed-dose combination: A case report.

BACKGROUND: Two-drug regimens antiretroviral therapies are increasingly prescribed to HIV patients, as they are recommended by international guidelines, and they show an excellent efficacy, safety, and tolerability profile. Regimens administered as single tablets (STRs) are usually preferred by patients and they are associated with higher adherence. CASE REPORT: We report two cases of drug-induced hypersensitivity (DIH) that occurred after switching from dolutegravir (DTG) plus rilpivirine (RPV) in separate pills to a fixed dose combination containing the same molecules (DTG/RPV; Juluca®). Following the DIH event, DTG/RPV coformulation was discontinued. At symptomatic resolution, they continued to receive DTG plus RPV in separate pills uneventfully. The component present only in the DTG/RPV coformulation was iron oxide red (E172), contained in the film-coating. Iron oxide red is an approved colorant, used as drug excipient. Patch test with DTG/RV coformulation performed several months after the DIH event was negative. Drug allergy to excipients remains underappreciated and underreported and frequently leads to inappropriate medication discontinuation. CONCLUSION: Our case underscores the role of meticulous medication allergy history in differentiating true medication allergy from excipient allergy. This observation may be useful in the era of antiretroviral simplification to two-drug regimens.

Diagnostic accuracy of vaccine and vaccine excipient testing in the setting of allergic reactions to COVID-19 vaccines: A systematic review and meta-analysis.

For persons with immediate allergic reactions to mRNA COVID-19 vaccines, skin testing (ST) to the vaccine/excipients (polyethylene glycol[PEG] and polysorbate 80 [PS]) has been recommended, but has unknown accuracy. To assess vaccine/excipient ST accuracy in predicting all-severity immediate allergic reactions upon re-vaccination, systematic review was performed searching Medline, EMBASE, Web of Science, and the WHO global coronavirus database (inception-Oct 4, 2021) for studies addressing immediate (≤4 h post-vaccination) all-severity allergic reactions to 2nd mRNA COVID-19 vaccination in persons with 1st dose immediate allergic reactions. Cases evaluating delayed reactions, change of vaccine platform, or revaccination without vaccine/excipient ST were excluded. Meta-analysis of diagnostic testing accuracy was performed using Bayesian methods. The GRADE approach evaluated certainty of the evidence, and QUADAS-2 assessed risk of bias. Among 20 studies of mRNA COVID-19 first dose vaccine reactions, 317 individuals underwent 578 ST to any one or combination of vaccine, PEG, or PS, and were re-vaccinated with the same vaccine. Test sensitivity for either mRNA vaccine was 0.2 (95%CrI 0.01-0.52) and specificity 0.97 (95%CrI 0.9-1). PEG test sensitivity was 0.02 (95%CrI 0.00-0.07) and specificity 0.99 (95%CrI 0.96-1). PS test sensitivity was 0.03 (95%CrI 0.00-0.0.11) and specificity 0.97 (95%CrI 0.91-1). Combined for use of any of the 3 testing agents, sensitivity was 0.03 (95%CrI 0.00-0.08) and specificity was 0.98 (95%CrI 0.95-1.00). Certainty of evidence was moderate. ST has low sensitivity but high specificity in predicting all-severity repeat immediate allergic reactions to the same agent, among persons with 1st dose immediate allergic reactions to mRNA COVID-19 vaccines. mRNA COVID-19 vaccine or excipient ST has limited risk assessment utility.

Do generic drugs cause hypersensitivity?

Generic drugs may differ from brand-name drugs in nature and quantity of excipients. Hypersensitivity to generic drugs is a subject of growing importance given their key role in healthcare spending policies, however, a review of published data highlighted that relevant data is sparse. No scientific rationale has emerged for labelling patients allergic to all generic drugs, and hypersensitivity to generic drugs may rather be explored on a case-by-case basis. In the case of hypersensitivity without any change in medication, it is advisable to check for a switch from a brand-name to a generic drug, and if hypersensitivity to a generic drug is suspected, its composition must be checked.

New insight into the importance of formulation variables on parenteral growth hormone preparations: potential effect on the injection-site pain.

Reducing injection-site pain (ISP) in patients with chronic conditions such as growth hormone deficiency is a valuable strategy to improve patient compliance and therapeutic efficiency. Thus understanding different aspects of pain induction following subcutaneous injection of biotherapeutics and identifying the responsible factors are vital. Here we have discussed the effects of formulation's viscosity, concentration, osmolality, buffering agents, pH, and temperature as well as injection volume, dosing frequency, and different excipients on ISP following subcutaneous injection of commercially available recombinant human growth hormone products. Our literature review found limited available data on the effects of different components of parenteral rhGH products on ISP. This may be due to high cost associated with conducting various clinical trials to assess each excipient in the formulation or to determine the complex interactions of different components and its impact on ISP. Recently, conducting molecular dynamics simulation studies before formulation design has been recommended as an alternative and less-expensive approach. On the other hand, the observed inconsistencies in the available data is mainly due to different pain measurement approaches used in each study. Moreover, it is difficult to translate data obtained from animal studies to human subjects. Despite all these limitations, our investigation showed that components of parenteral rhGH products can significantly contribute to ISP. We suggest further investigation is required for development of long acting, buffer-free, preservative-free formulations. Besides, various excipients are currently being investigated for reducing ISP which can be used as alternatives for common buffers, surfactants or preservatives in designing future rhGH formulations.

COVID vaccination can be performed in patients with a history of allergic reactions to the vaccines or their components: experience from a specialist clinic in South Australia.

BACKGROUND: The development of vaccines against SARS-CoV2 has been a key public health response to the COVID-19 pandemic. However, since their introduction, there have been reports of anaphylactic reactions to vaccines in individuals with history of allergic reactions to other vaccines, excipients or to COVID vaccines. AIM: A dedicated adult COVID vaccine allergy clinic with a standardised allergy testing protocol was set up to investigate safety and suitability of available COVID vaccines in Australia. METHODS: Patients referred to a state-wide COVID-19 vaccine allergy clinic between March and August 2021 with a history of allergy underwent skin-prick testing and intradermal testing to both available vaccine formulations (BNT162b2 and ChAdOx1-S), excipients (polyethylene glycol and polysorbate 80), excipient-containing medications and controls. Basophil activation testing was conducted in few subjects with convincing history of immediate type reactions. RESULTS: Fifty-three patients underwent testing for possible excipient allergy (n = 19), previous non-COVID vaccine reaction (n = 13) or previous reaction to dose 1 of COVID-19 vaccine (n = 21). Patients were predominantly female (n = 43, 81%), aged 18-83 (median 54) years. Forty-four patients tested negative and 42 of these received at least their first dose of a COVID-19 vaccine. Nine patients tested positive to excipients or excipient-containing medication only (n = 3), or vaccines (n = 6). Five patients were positive to just BNT162b2, 3/5 have been vaccinated with ChAdOx1-S. One who was skin test positive to both vaccines, but negative BAT to ChAdOx1-S was successfully vaccinated with ChAdOx1-S. CONCLUSION: Even in a high-risk population, most patients can be vaccinated with available COVID-19 vaccines. This paper reports local experiences using a combined allergy testing protocol with skin testing and BAT during the pandemic.