Cow’s Milk Protein Allergy: The Hidden Danger of Medicines’ Excipients

In patients with a cow’s milk protein allergy, the presence of these allergens in medicines, even in trace amounts, can trigger serious allergic reactions. The study of milk-related excipient prevalence in 165 antiasthmatic medicines, based on the information included in the Summary of Product Characteristics, revealed the presence of lactose in more than one third of these medicines. Since lactose may suffer cross-contamination with cow’s milk protein, these results are an alert to health professionals.

AB0649 INFECTION PROFILE OF IMMUNE-MODULATORY DRUGS USED IN AUTOIMMUNE DISEASES: ANALYSIS OF SUMMARY OF PRODUCT CHARACTERISTIC DATA

Background:The number of immune-modulatory drugs used to treat immune-mediated inflammatory diseases (IMIDs) has exponentially increased in recent decades. While effective in controlling disease, serious infection remains a concern.Accurate information on immune-modulatory drugs, including infections, is required to guide prescribing decisions. The “summary of product characteristics” (SmPC) by the European Medicines Agency (EMA) provides a useful repository of information on adverse events e.g. infections, from clinical trials and post-marketing pharmacovigilance (1).To date, no comparison has been undertaken on reported infection frequencies across SmPCs for immune-modulators.Objectives:To compare infection frequency, site and type across the most commonly-prescribed immune-modulatory drugs used to treat IMIDs, using information provided by SmPCs.Methods:A drug was included if licensed in Europe for treatment of one of the following: rheumatoid arthritis, axial spondyloarthritis, connective tissue disease, autoimmune vasculitis, autoinflammatory syndromes, inflammatory bowel disease (Crohn’s and ulcerative colitis), psoriasis, multiple sclerosis and other rarer conditions.The Electronic Medicines Compendium (EMC) was searched for commonly prescribed immune-modulatory drugs used for the above indications. SmPC documents were manually searched for information on infection frequency, extracted from sections 4.4 and 4.8. Infection frequency was recorded as per convention in the SmPC: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) (1), for each drug. Information was further extracted on infection site (e.g. respiratory, skin etc), type (e.g. bacterial, viral etc) and individual pathogenic organisms.25% of included SmPCs were screened and extracted by a second reviewer. Disagreements were resolved with input from a third reviewer.Results:In total, 39 drugs were included, used across 20 indications: nine conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), six targeted synthetic DMARDs (tsDMARDs; four Janus kinase [JAK] inhibitors, two sphingosine 1-phosphate receptor modulators) and 24 biologic DMARDs (17 cytokine-targeted; seven cell-targeted).Twelve sites of infection were recorded. Minimal or no site information was available for most csDMARDs and siponimod, certolizumab pegol and rituximab. The most common sites of infection are listed by drug group in Figure 1. Upper respiratory tract was the most common site, especially with bDMARDs. Lower respiratory, ear/nose/throat (including sinusitis) and urinary tract infections were moderately common, with clustering within drug groups. No drugs reported risk of cardiac infections; the eye, musculoskeletal, neurological, oral and reproductive sites were the least commonly-reported sites of infection.Infection data for 27 distinct pathogens were recorded, the majority viruses, especially with bDMARD use. Herpes simplex and zoster were the most frequently listed (mainly with bDMARDs and tsDMARDs), followed by influenza. Common non-viral causes of infection were candida and tinea species.Variable or absent reporting was noted for opportunistic infections (e.g. tuberculosis and fungi) and certain high-prevalence viruses e.g. Epstein-Barr.Conclusion:The SmPC literature reports differences in infection risk, by site and pathogen, between immune-modulatory drugs. The findings can be used to visualise differences and aid treatment decisions. However, some of the patterns we have shown lack face-validity to clinicians familiar with real-world safety data. The data fail to capture risk of rare infections, are likely skewed by trial selection criteria, varying number of trials per drug and quirks of individual study-reporting methodologies.The findings highlight the need for robust post-marketing pharmacovigilance studies.References:[1]A Guideline on Summary of Product Characteristics Module 1.3. 2008.Disclosure of Interests:None declared.

Automatic Extraction of Adverse Drug Reactions from Summary of Product Characteristics

The summary of product characteristics from the European Medicines Agency is a reference document on medicines in the EU. It contains textual information for clinical experts on how to safely use medicines, including adverse drug reactions. Using natural language processing (NLP) techniques to automatically extract adverse drug reactions from such unstructured textual information helps clinical experts to effectively and efficiently use them in daily practices. Such techniques have been developed for Structured Product Labels from the Food and Drug Administration (FDA), but there is no research focusing on extracting from the Summary of Product Characteristics. In this work, we built a natural language processing pipeline that automatically scrapes the summary of product characteristics online and then extracts adverse drug reactions from them. Besides, we have made the method and its output publicly available so that it can be reused and further evaluated in clinical practices. In total, we extracted 32,797 common adverse drug reactions for 647 common medicines scraped from the Electronic Medicines Compendium. A manual review of 37 commonly used medicines has indicated a good performance, with a recall and precision of 0.99 and 0.934, respectively.

Considering additive effects of polypharmacy

Summary Background Potential additive effects of polypharmacy are rarely considered in adverse events of geriatric patients living in long-term care facilities. Our aim, therefore, was to identify adverse events in this setting and to assess plausible concomitant drug causes. Methods A cross-sectional observational study was performed in three facilities as follows: (i) adverse event identification: we structurally identified adverse events using nurses’ interviews and chart review. (ii) Analysis of the concomitantly administered drugs per patient was performed in two ways: (ii.a) a review of summary of product characteristics for listed adverse drug reactions to identify possible causing drugs and (ii.b) a causality assessment according to Naranjo algorithm. Results (i) We found 424 adverse events with a median of 4 per patient (range 1–14) in 103 of the 104 enrolled patients (99%). (ii.a) We identified a median of 3 drugs (range 0–11) with actually occurring adverse events listed as an adverse drug reaction in the summary of product characteristics. (ii.b) Causality was classified in 198 (46.9%) of adverse events as “doubtful,” in 218 (51.2%) as “possible,” in 7 (1.7%) as “probable,” and in 1 (0.2%) adverse event as a “definitive” cause of the administered drugs. In 340 (80.2%) of all identified adverse events several drugs simultaneously reached the highest respective Naranjo score. Conclusion Patients in long-term facilities frequently suffer from many adverse events. Concomitantly administered drugs have to be frequently considered as plausible causes for adverse events. These additive effects of drugs should be more focused in patient care and research.

P62 Cyclophosphamide and maintenance mycophenolate mofetil for the treatment of anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis in a paediatric patient

BackgroundAnti-NMDAR encephalitis is one of the commonest known types of autoimmune encephalitis with an increasing recognition in the paediatric population.1 2 It is characterised by abnormal behavioural and cognitive symptoms, seizures and movement disorders where treatment failure or failure to treat can result in long term disabilities or mortality.1A 4-year-old patient with a background of autism was admitted to the paediatric intensive care unit (PICU) due to encephalitis with convulsive status epilepticus where he remained intubated for 22 days and was later diagnosed with anti-NMDAR encephalitis. The patient had persistent abnormal choreoathetoid movements and intermittent seizures despite multiple anti-epileptics, two courses of corticosteroids, two courses of intravenous immunoglobulin, two cycles (10 sessions per cycle) of plasmapheresis and a course of weekly rituximab. Due to the lack of response from these initial pharmacological interventions, the use of cyclophosphamide and mycophenolate mofetil was considered. Cyclophosphamide and mycophenolate mofetil inhibits the proliferations of B- and T-lymphocytes3 4 which acts as the basis of its immunosuppressive actions. However, available evidence on the dosing and monitoring information in the paediatric population for this unlicensed indication is limited.Pharmacy ContributionsAfter discussion with the multi-disciplinary team (MDT) with extensive input from the paediatric neurologist, a literature search was conducted to determine an appropriate dosing regimen. As this was an off-label use, the paediatric neurologist and the attending consultant took clinical responsibility. Intravenous cyclophosphamide was started at 750 mg/m2 once a month for three cycles and oral mycophenolate mofetil was started at 600 mg/m2 twice a day as maintenance therapy a week after. The specialist pharmacist explained the individualised treatment plan for the patient to the MDT and ensured measures (hydration and mesna) for the prevention of cyclophosphamide-induced haemorrhagic cystitis were appropriately prescribed on the electronic prescribing system with the appropriate timings of administration. Monitoring parameters to determine adverse effects were closely observed. A local guideline was developed during the treatment cycles to ensure all members of the MDT were following the correct procedures.OutcomeThe patient responded to cyclophosphamide and clinically improved after the completion of three cycles of monthly treatment. Maintenance mycophenolate mofetil was subsequently stopped a month after the last cycle of cyclophosphamide due to neutropenia. A review of the patient one year after first presentation shows the patient is almost back to their baseline.Lessons LearnedAlthough there are potentially serious side effects, cyclophosphamide and mycophenolate mofetil has been successful in the treatment of anti-NMDAR encephalitis. The recovery of this patient required extensive support from the entire MDT.ReferencesNHS England. Clinical Commissioning Policy: Rituximab for second line treatment for anti-NMDAR autoimmune encephalitis (all ages). March 2018.Salvucci A, Devine IM, Hammond D, et al. Pediatric anti-NMDA (N-methyl D-Aspartate) receptor encephalitis. Pediatric Neurology 2014;50:507–510.Summary of Product Characteristics. Cyclophosphamide 1000 mg Powder for Solution for Injection or Infusion. Last updated on eMC on 27-Jun-2017. Available at https://www.medicines.org.uk/emc/product/3525/smpc# [Accessed 04 July 2019]Summary of Product Characteristics. CellCept 1 g/5 mL powder for oral suspension. Last updated on eMC on 16-Mar-2018. Available at https://www.medicines.org.uk/emc/product/1569/smpc [Accessed 04 July 2019]

P027 Teicoplanin: evaluation of serum concentrations

AimThe trust has implemented the use of therapeutic drug monitoring (TDM) of teicoplanin on intensive care following research that identified great variability in population pharmacokinetics in children.1–3 The summary of the research available showed that patients are not achieving target concentrations. This retrospective audit aimed to evaluate whether patients were achieving target serum concentrations. It also evaluated whether teicoplanin TDM was correctly completed for each patient. The following objectives were set based on grey literature and the Summary of Product Characteristics:4 Evaluate if serum concentrations are being taken on or after day 4 post initiation (steady state), and within 1 hour pre-dose (trough) Assess if serum concentrations reach target concentration with standard initial BNFC dosing appropriate for the indication of treatment.MethodsA retrospective report of teicoplanin serum concentrations was provided by the biochemistry labs covering a 6 month period. This report was used to identify the patients for the audit. For each patient: dose information, times and clinical particulars were obtained via the electronic prescribing system, Meditech version 6. If needed, clinical records were obtained from the medical records archive.Results71 serum concentrations were identified. 11 were excluded due to unobtainable or incomplete data. Serum concentrations were then evaluated for accuracy. The criteria set for determining accuracy were: Serum concentration taken on or after day 4 post initiation (steady state) Serum concentration taken within 1 hour pre dose (trough) Patient prescribed correct BNFC dosing regimen 55% (n=33) of patients had all 3 criteria met for an accurate concentration to be determined. This meant 45% of our patients serum concentrations could not be used to accurately evaluate if current dosing regimens promptly achieve target concentrations. Using the patients’ serum concentrations that followed the above criteria, it was found that 64% of these patients did not reach their desired target concentration. This included patients with: endocarditis (n=5) – aiming for trough greater than 30 mg/L cystic fibrosis (n=1) – aiming for trough greater than 20 mg/L other infections such as sepsis (n=27) – aiming for trough greater than 15 mg/L No patient included in this audit that required a higher target concentration reached their target before the first serum concentration.ConclusionIt is evident that teicoplanin TDM, which is still in its infancy at the trust, requires further support to improve practice. From the serum concentrations that were carried out correctly, this audit begins to illustrate a number of issues surrounding teicoplanin dosing in paediatric patients, especially those with difficult to treat infections. Further research is required to assess how these correlate to clinical outcome in practice as well as evaluating patients not in an intensive care setting. This study can be a driving force for a larger scale study to be carried out so that recommendations can be established and a change of practice can be implemented.ReferencesRamos-Martín V, Paulus S, Siner S, et al. Population Pharmacokinetics of Teicoplanin in Children. J Antimicrob. Chemother 2014;58: 6920–6927Harding I, Macgowan AP, White LO, et al. Teicoplanin therapy for Staphylococcus aureus septicaemia: relationship between pre-dose serum concentrations and outcome. J. Antimicrob. Chemother 2000;45:835–841.Reed MD, Yamashita TS, Myers CM, et al. The pharmacokinetics of teicoplanin in infants and children. J. Antimicrob. Chemother 1997;39:789–796.Targocid 400mg [Internet]. Targocid 400mg - Summary of Product Characteristics (SmPC) - (eMC). Available from: https://www.medicines.org.uk/emc/product/2927 (Accessed 20 February 2018)

P4 Outcome following switch between brand name and generic tacrolimus in paediatric population

IntroductionGeneric preparations of drugs are often cheaper than brand names and offers significant cost benefits. For many medicines, a switch between preparations can be done with little or no monitoring. Tacrolimus prescription, however, provides an interesting challenge due to its narrow therapeutic window and requires careful medical supervision and therapeutic monitoring while switching. Adoport1 is a generic tacrolimus preparation introduced to the market after the exclusivity period for Prograf2 ended. At present there is limited evidence to show the effects of the switch between formulations in paediatric patients. In 2015, Nottingham Children’s Renal Unit undertook to switch all existing paediatric kidney transplant and nephrotic patients on Prograf to Adoport and we herewith present the effects on patients and their Tacrolimus levels.MethodPrescriptions for tacrolimus are dispensed and delivered by a homecare provider on a three monthly basis. Patients were given written and verbal advice to switch from Prograf to the same dose of Adoport two weeks before their next clinical appointment. After taking a stock of their existing Prograf supply, a prescription was given to ensure the patient did not run out of Prograf until their switch date and had enough Adoport until the following prescription was due. The Tacrolimus level was then reviewed by the patient’s doctor at their clinic appointment and dose adjustments were made if necessary as per standard of care. We reviewed data for Tacrolimus levels in the 3 months before and after the switch and assessed for any clinical variation in immunosuppression.Results36 patients were switched from Prograf to Adoport. One patient developed hair loss and requested to go back onto Prograf, all other patients tolerated the switch well. There was no significant change in the tacrolimus levels of the population following the switch (p=0.02). There was no significant change in creatinine of the population following the switch (p=0.02). One patient required a dose adjustment following the switch.ConclusionThis study assessed the clinical outcomes for paediatric patients switching from Prograf to Adoport. We noted stable Tacrolimus levels in most patients following the switch and similar therapeutic effectiveness. The majority of patients tolerated the switch well. This resulted in a cost saving for NHS England from which a gain share was negotiated to benefit Nottingham University Hospitals NHS Trust. Our outcome data therefore support the use of Adoport in place of Prograf as a potential cost-saving measure.ReferencesSummary of Product characteristics Astella Pharma Ltd. Prograf 0.5 mg, 1 mg, 5 mg Hard capsules 2 November 2015. www.medicines.org.uk [Accessed: 30 April 2016].Summary of Product characteristics Sandoz Ltd. Adoport 1 mg capsules 18 August 2015. www.medicines.org.uk [Accessed: 30 April 2016].