Lack of child-friendly dosage forms and strengths often leads to manipulation of medicines at hospital units or by caregivers in the home setting. One alternative to manipulating dosage forms is the use of extemporaneous preparations. In Sweden, these are produced according to good manufacturing practice by a few extemporaneous pharmacies.To compare frequencies of patients administered extemporaneous preparations in two separate years, 10 years apart.This registry-based study describes and compares the frequency of extemporaneous oral preparations administered to paediatric patients in 2009 and 2019 at a Swedish university hospital.The study included 117 023 oral administrations (to 4905 patients) and 128 638 oral administrations (to 4718 patients) from 2009 and 2019, respectively.The frequency of inpatients administered one or more extemporaneous preparations increased from 22% in 2009 to 40% in 2019 (p<0.0001). The increase was observed in all age groups. The use of some active pharmaceutical ingredients increased (eg, captopril, clonidine, hydrocortisone, melatonin and propranolol), and some active pharmaceutical ingredients decreased between the study years (eg, midazolam and sildenafil).The introduction of new authorised products has decreased the need for manipulation or extemporaneous preparations in some therapeutic groups. There remains, however, a pronounced lack of commercially available child-friendly dosage forms and suitable strengths enabling safe administration of medicines to children, indicated by the large percentage of patients receiving at least one extemporaneous preparation.
Opioids are common drugs for pain treatment in preterm newborn infants, in spite of several adverse effects. Constipation is a frequent problem when opioids are used in both adults and neonates. Although several studies indicate that the oral administration of naloxone hydrochloride (NH) improves intestinal motility during opioid therapy, there is still a lack of evidence in newborns.The aim of this study was to assess the efficacy of NH against reduced intestinal motility during opioid treatment.A retrospective cohort study was performed. We analysed the medical records of fifteen infants (Group 1) treated with continuous morphine (MO) infusion and fourteen infants (Group 2) treated with both oral NH (3 microg/kg 4 times daily) and MO.There was no statistically significant difference in the total MO dose. Infants treated both with NH and MO had a tendency to improve their mean stool frequency/day. A statistically significant improvement was observed in the mean total food intake (mL/kg/day) of the infants treated with NH (p = 0.014). No difference in the mean food retention between the two groups was observed.Orally administrated NH seems to improve intestinal motility resulting in increased food intake/day and improved stool frequency/day in premature newborn infants treated with MO. Further studies are needed to corroborate these findings.
Abstract Objective To determine the incidence of drug-related therapy problems (DRTPs) among patients obtaining medicines for allergy, asthma or pain. Method Problem detection interventions at the pharmacies were carried out as project-like activities. Pharmacy staff members used open-ended questions to detect all DRTPs in patients presenting prescriptions for medicine for allergy, asthma and pain and in people buying over-the-counter (OTC) medicines for allergy. The data were collected under regular health care conditions and the study can therefore be considered as a survey of the epidemiology of DRTPs among the selected groups of patients. Setting Swedish community pharmacies during two one-year nationwide disease management programmes on allergy and pain. Key findings Of the 44,504 patients with prescriptions registered in the study, 13,895 (31 per cent) with DRTPs were detected. Of 1,135 people buying OTC medicines for hay fever/pollen allergy, 144 (13 per cent) with DRTPs were detected. Conclusion The study indicates that about one-third of patients with prescriptions have DRTPs. Only a fraction of all DRTPs are apparently discovered in the regular dispensing process at the pharmacies. Pharmacy staff need to use more active interventions, such as dialogue with open-ended questions, to efficiently identify and help patients with DRTPs.
The aim of this retrospective study was to investigate the clinical practice, i.e. the frequency of use and the treatment strategies, for acid reducing drugs to neonates in a Swedish hospital.Retrospective reviews of charts and interviews with nurses at the neonatal wards of Karolinska University Hospital were performed to identify difficulties that might occur with drug administration. All patients admitted over a 2-month period were included. Main outcome measure were the number of patients treated with acid reducing drugs and the dosages.Nine out of 215 patients (4.2%) received an acid reducing drug. Patients treated with acid reducing drugs had significantly lower birth weight, lower gestational age and longer duration of hospitalization. Eight of the patients were treated with omeprazole. One of these patients started treatment with omeprazole but continued later on with ranitidine. One patient was exclusively treated with ranitidine. The doses of omeprazole (intravenous or oral administration) were within the range 0.16-1.26 mg/kg/day.A wide variation in treatment regimens of acid reducing drugs is given to newborn infants. The percentage of treated children was much lower than earlier reports from the US and UK. No conclusions can be drawn as to whether the doses and dosing intervals used give sufficient acid suppression, since the effect of the therapy was not recorded. The present study is only retrospective and data are not truly comparable with other studies. Further studies are therefore warranted to evaluate effective doses and pharmacokinetics of acid reducing drugs in newborn infants.
A simple and rapid method for Shiga toxin purification based on specific binding to the Galα1 → 4Galβ1 → 4Glc globotrioside trisaccharide covalently linked to polyacryl/polyvinyl (Fractogel) has been developed. A cell‐free sonicate‐filtrate of Shigella dysenteriae type 1, strain 114Sd was passed over the globotrioside‐Fractogel column, and bound toxin eluted with 6 M guanidine‐HCl. A yield of 36 mg pure toxin/1 sonicate‐filtrate was otained, i.e. a one step 1224‐fold purification. The recovery of biologically active toxin was 87%. The toxin was purified to homogeneity as shown by native PAGE and SDS‐PAGE.
Providing medicines for children with different ages, body weights and capacities poses clinical challenges. There is currently a lack of appropriately formulated medicines with suitable dosage forms and strengths to account for these variations including differences in absorption, distribution, metabolism and elimination of compounds. It is often necessary to crush and dissolve adult medicines to provide the prescribed dose, but healthcare staff or caregivers frequently must do this without supporting data in the market authorisations, which leads to uncertainty about the dose that is administered. Previous studies on how to dissolve a tablet and withdraw part of the solution found that the amount of acetylsalicylic acid recovered varied from 3% to 99%, depending on whether dispersible or not dispersible tablets were used and the extent of mixing.1, 2 In this report, we reflect on data from our laboratory and previous studies.3, 4 The aim was to discuss two additional important aspects for dissolving tablets and using part of the solution. These were the proportion of the active pharmaceutical ingredients (APIs) in a tablet and the aqueous solubility of the active substance in relation to the intended concentration after dispersing the tablet in water according to a frequently used paediatric medicine preparation technique. The first aspect is the amount of API in relation to the excipients, the non-active ingredients which are added to achieve the required tablet size and properties. High-dose APIs account for most weight of a tablet and one example is paracetamol, which accounts for 90% of the tablet (Figure 1). Low-dose APIs, with a high proportion of nonactive ingredients include clonidine where the API is only 0.08% of a tablet. This makes visual examination of low-dose tablet dissolution difficult, as only the successful dissolution of the nonactive ingredients is examined. It is likely that healthcare providers rarely reflect upon whether a tablet contains a low or a high dose API. The second aspect is the maximum amount of API possible to dissolve (aqueous solubility) in relation to the intended concentration when a tablet is dispersed in water. If the APIs in Figure 1 were dispersed as tablets in 10 mL of water, for four out of the five substances, the solubility is lower than the intended concentration. Dispersing clemastine, with an aqueous solubility of 0.0004 mg/mL,5 it may look like most of the material has dissolved when a 1 mg tablet is placed in 10 mL of water, with the intended concentration of 0.1 mg/mL. The clear liquid lying above the solid, settled material, can however never contain a higher concentration than the aqueous solubility (0.0004 mg/mL) unless the pH is adjusted or solubilising agents are added. There is a significant risk of underdosing if this procedure is performed, and part of the solution is administered. The major challenge for healthcare professionals to understand and assess this relates to the availability of information. In public databases such as PubChem,5 information about aqueous solubility can be found but it requires some specialist physicochemical knowledge and pharmaceutical skills to evaluate. There are both calculated, and experimentally measured, solubilities stated, and the pH and temperature of the dissolution media can affect solubility. Often, conventional tablets do not contain solubilising nonactive ingredients, rather the choice of specific salts is used to improve the solubility. In the example of clemastine above, the API is selected as a fumarate salt in the licensed product, likely providing a higher solubility; however, the information is not readily available in public literature. Another example, paracetamol is available as a licensed 24 mg/mL oral solution in Sweden, which suggests that a 250 mg tablet dissolved in 10 mL of water would yield a 25 mg/mL solution. However, paracetamol has an aqueous solubility of around 14 mg/mL at room temperature5 and trying to dissolve such a tablet will leave undissolved material. The licensed oral solution, however, includes nonactive substances to increase the solubility to the labelled concentration and above. The study with acetylsalicylic acid also showed the importance of using nonactive ingredients, such as calcium carbonate, to achieve better homogeneity when dissolving tablets.2 If the APIs in Figure 1 were dispensed as tablets in 10 mL of water, the only soluble product would be clonidine with a solubility of 50 mg/mL.5 Taking a portion of a dispersed tablet with an API with sufficient solubility can be safe but relies on the API being uniformly distributed in the liquid. An additional complication in this case is that the tablet could contain nonactive ingredients, such as cellulose, which are insoluble in water. The resulting hazy fluid could falsely be interpreted as an insoluble API. In the absence of appropriate, licensed, products for children, we propose the use of extemporaneously prepared products. The safe handling of APIs with narrow therapeutic windows is of the upmost concern. Tablets should only be dissolved in water, for partial administration, if the aqueous solubility is well above the intended concentration. None. None.
Introduction: To investigate the dosing accuracy using split tablets in paediatric patients. Methods: Five brands of tablets (Alvedon ® (paracetamol), Catapresan ® (clonidine), Hydrocortone ® (hydrocortisone), Prednisolon ® (prednisolon) and Tavegyl ® (clemastine) were split into halves and quarters by hand or by using a tablet splitter. The resulting halves and quarters were weighed. Results: Three out of the five tablet brands passed the test in the Ph. Eur. (European Pharmacopoeia) for subdivision of tablets when split once and when split twice to yield quarters only one of the tablets passed the test. When also applying the limit for relative standard deviation (RSD) from the US Pharmacopoeia only one of the tablet halves passed and the other two was just outside the limit. None of the tablet quarters passed the RSD limit. Conclusion : Our results indicate that tablets larger than 8 mm might be split once. Tablets should not be split more than once, due to uncertainty in dose accuracy. There is a need for more commercially available age-appropriate formulations. Extemporaneously prepared formulations should be considered as an alternative to the use of split tablets. Key words: Dosing accuracy, Manipulation of drugs, Paediatric patients, Subdivision of tablets, Tablet splitting
The use of off-label drug and manipulation are very common in paediatrics, since there is a lack of drugs in suitable strengths and child-friendly dosage forms. A manipulation is the physical alteration of a drug dosage form with the purpose to extract and administer the prescribed proportion of a drug dose. In an earlier study, we concluded that tablets should not be split to receive a smaller dose due to the irregularity of the resulting halves, but we still lack information on how common this procedure is.
Purpose
To study the frequency of manipulated medicines administered to paediatric inpatients at a large children's hospital during 1 year.
Material and methods
To answer this question, we collected data for all administered doses during 12 months at the paediatric wards at our children's hospital, from a hospital-based register. All administered doses where the number of tablets or suppositories were decimal were added and calculated as a percentage of all administered doses. Data were anonymous but information regarding sex, age, hospital ward and number of drugs per patient were available and were analysed.
Results
During 1 year, approximately 4 50 000 doses of medicine are administered to paediatric patients in our children's hospital. Preliminary results show that 7% of all administered doses are for a decimal number of tablets or suppositories in all age groups. The medicines that most frequently were prescribed and administered as decimal numbers were clobazam tablets and ibuprofen suppositories.
Conclusion
Our results clearly illustrate the need for more child-appropriate medicines/strengths. Most often there is a lack of knowledge of how manipulation of medicines influences the dosing accuracy and often we do this to our most vulnerable patients. Further studies are needed to investigate the relation between manipulation of medicines and dosing accuracy, and to establish best practice when manipulation is necessary. No conflict of interest
Studies on frequencies of manipulated medicines in paediatric care are common, but there is little knowledge of experiences of pharmacists and registered nurses in this area. The aim of this study was to explore registered nurses' and pharmacists' reasoning in the manipulation of medicines to paediatric inpatients.Semistructured interviews with twelve registered nurses and seven pharmacists were performed at a Swedish paediatric university hospital. The interviews were transcribed verbatim and analysed using content analysis.Four major categories emerged from the analysis of the interviews: medicines management, knowledge, consulting others and organisation. Medicines management involved the process of drug handling, which is prescribing, reconstitution or manipulation and administration. Knowledge concerned both the knowledge base and how healthcare personnel seek information. Consulting others involved colleagues, registered nurses and pharmacists, between registered nurses, pharmacists and physicians and between registered nurses, pharmacists and caregivers. Organisation covered documentation, time and working environment.Both pharmacists and registered nurses stated that manipulation of medicines to paediatric patients was often necessary but felt unsafe due to lack of supporting guidelines. Pharmacists were natural members of the ward team, contributing with specific knowledge about medicines and formulations.
