Prescribing for off-label use and unauthorized medicines in three paediatric wards in Finland, the status before and after the European Union Paediatric Regulation.

WHAT IS KNOWN AND OBJECTIVE: The European Paediatric Regulation aims to reduce off-label use of medicines in paediatric pharmacotherapy. Prescribing for off-label use and unauthorized medicines was common in the paediatric wards of the Kuopio University Hospital in 2001. To evaluate the possible impact of the Regulation on the prevalence and the frequency on such prescribing, we repeated the study in 2011 as it was conducted 10 years earlier. METHODS: In this prospective study, the prescriptions for patients below 18 years of age were reviewed during a 2-week period in each of the three wards; neonatal intensive care unit, general paediatric ward and paediatric surgical ward in April and May 2011. The medicine's authorizing status of all prescriptions was determined according to the approved summary of product characteristics valid during the study in Finland. Data concerning unauthorized medicines were also recorded and classified. RESULTS: Out of the entire study population of 123 patients, 119 received a total of 1054 prescriptions in 2011. The proportion of patients with at least one prescription for off-label use or for an unauthorized medicine was significantly higher, 79% (n = 97) in 2011, compared to 58% in 2001 (P < 0·001). For newborns, significantly more prescriptions were for off-label use in 2011 than in 2001 (51% vs. 22%; P < 0·001). The proportion of prescriptions for unauthorized medicines was significantly higher in children below 2 years of age than in older children in both years (21% vs. 5% in 2011 and 24% vs. 3% in 2001, P < 0·001). WHAT IS NEW AND CONCLUSION: The prescribing for off-label use and unauthorized medicines was more prevalent in 2011 than in 2001. This indicates that the recent legislation has had only minor or no impact on the authorizing status of medicines commonly used in paediatric inpatients in specialized care.

Stability of an epidural analgesic admixture of levobupivacaine, fentanyl and epinephrine.

WHAT IS KNOWN AND OBJECTIVE: Admixtures of levobupivacaine, fentanyl and epinephrine are increasingly used in epidural pain management. Neither the compatibility nor the stability of levobupivacaine with fentanyl and epinephrine is known and therefore we examined the chemical, physical and microbiological stability of levobupivacaine-fentanyl-epinephrine and levobupivacaine-fentanyl admixtures prepared in the hospital pharmacy. METHODS: Fentanyl and epinephrine were added into commercial levobupivacaine infusion bags. The components were analysed by HPLC and assays were performed up to 60 days of storage of the bags both protected and exposed to light at room temperature and stored in the refrigerator. In addition, sterility, bacterial endotoxins, organoleptic properties, pH and mass of the admixture were determined. RESULTS AND DISCUSSION: Levobupivacaine, fentanyl and epinephrine concentrations remained within the ± 10% specification limit during 60 days storage in the refrigerator in tightly closed secondary packing material and protected from light and for at least 40 days at room temperature. The degradation of epinephrine exceeded 10% within 60 hours when exposed to light. The solutions were microbiologically and physically stable. WHAT IS NEW AND CONCLUSION: Epidural analgesic admixtures of levobupivacaine and fentanyl with or without epinephrine have to be stored in a tightly closed secondary package protected from light. The extended stability, up to 60 days, in a refrigerator enables the centralized preparation in the hospital pharmacy.

Off-label and unlicensed drug prescribing in three paediatric wards in Finland and review of the international literature.

OBJECTIVES: In paediatric pharmacotherapy, many drugs are prescribed to be given in ways and for conditions not approved in the marketing authorization (MA). Thus, off-label prescribing of drugs with no MA is widespread in paediatric wards. However, drug MA status and clinical practices differ across countries. In this prospective study, we studied the prescribing of off-label and unlicensed drugs in three paediatric wards in a tertiary hospital in Finland. Furthermore, we reviewed previous published studies to provide an up-to-date international perspective on prescribing of off-label and unlicensed drugs for hospitalized children. METHODS: During a 2-week period, prescriptions for patients under 18 years of age (median age 1*6 years) in three wards; neonatal intensive care unit (NICU), general paediatric ward and paediatric surgical ward were recorded daily and drug-licensing status of all prescriptions was determined according to the approved summary of product characteristics. Published studies were retrieved through electronic searches, including MEDLINE (PubMed). RESULTS: Of the 141 children, 108 received 629 prescriptions. Of the 108 children with a prescription, 82 (76%) had at least one off-label or unlicensed drug prescribed; 79% in the NICU, 63% in the general ward and 91% in the surgical ward (P = 0*014). Of the 108 children with a prescription, 26 (24%) received prescriptions for licensed drugs, 71 (66%) received prescriptions off-label and 36 (33%) for unlicensed drugs. Of all 629 prescriptions, 321 (51%) were for licensed drugs, 226 (36%) for off-label and 82 (13%) for unlicensed drugs. International studies showed similar extents of off-label and unlicensed-drug prescribing. CONCLUSION: This study indicates that the use of off-label and unlicensed drugs is widespread in all the different paediatric wards surveyed and was as extensive as those reported for other countries.

Nifedipine capsules may provide a viable alternative to oral powders for paediatric patients.

BACKGROUND AND OBJECTIVE: To compare content uniformities between different sizes of extemporaneously compounded nifedipine oral powders and capsules, in order to find out if capsules could be used instead of oral powders as paediatric medications. METHODS: Actual content and content uniformity of extemporaneously compounded 1-mg nifedipine oral powders and capsules were evaluated by a high performance liquid chromatographic assay. Capsules and powders were prepared by triturating 10-mg nifedipine tablets with different amounts of lactose or microcrystalline cellulose with a mortar and pestle using a standard geometric dilution technique. Oral powders were weighed individually and capsules were filled by a hand-operated capsule-filling machine. Four different sizes of powders (500, 300, 100 and 50 mg) and three different sizes of capsules (numbers 1, 3 and 4) were prepared. Ten oral powders and 10 capsules from each batch were randomly selected and individually assayed for nifedipine amount. RESULTS AND DISCUSSION: The extemporaneously prepared nifedipine oral powders and capsules were within acceptable limits for content uniformity, as defined by the European Pharmacopoeia, but the results indicate that the loss of nifedipine during the preparation process may be considerable for both preparations. The concentration on nifedipine decreased while the total mass of the oral powder decreased. These results demonstrate that nifedipine oral powders can be replaced by capsules, whose contents are emptied for use, in paediatric medications. Compounding small capsules, such as size number 3 or 4, is acceptable when considering the average drug content. The total weight of the oral powder should be at least 300 mg. CONCLUSION: The preparation of nifedipine in all studied capsule sizes was safe with either lactose monohydrate or microcrystalline cellulose as excipients. Thus, emptied capsules seem to be a good choice for delivering a paediatric medication. The loss of nifedipine was considerable in oral powders with low total weight.

Enteral suspension of nifedipine for neonates. Part 1. Formulation of nifedipine suspension for hospital use.

OBJECTIVE: To formulate an oral suspension of nifedipine for paediatric use and to assess its content uniformity as well as the microbiological and physical stabilities of the hypromellose solution that was used in the formulation. METHOD: Six concentrations (0.5-3.0%) of hypromellose colloids and water as a blank were compounded with nifedipine, both as a powder and as crushed tablets, to a concentration of 1 mg/mL. Four different screening tests were used to find the most homogenous and dose-accurate combination. First, nifedipine suspensions were stored in vials for one month and visual homogenity of the redispersed suspensions was observed. Second, the homogenity of the suspensions was studied by measuring the nifedipine concentration from upper, middle and lower parts of the redispersed suspension. Next, the nifedipine concentration was measured from the suspensions immediately, 1 min and 2 min after shaking to ensure dose accuracy during the administration period. Finally, suspensions were packaged into oral disposable syringes and nifedipine concentrations were determined after one month of storage. Content uniformity of the packaged single-dose syringe suspensions was studied according to a method established by the European Pharmacopoeia. Microbiological stability, density, pH, osmolality, viscosity and surface tension of the hypromellose solution were studied over a 12-month storage period. RESULTS: From the results of the screening tests of hypromellose solution, 1.0% hypromellose was chosen as the vehicle for nifedipine enteral suspensions, made from both crushed tablets and nifedipine powder. Nifedipine suspensions made from hypromellose 1.0% were easiest to redisperse as a homogenous solution, and it also appeared best on visual inspection. The content uniformity of the suspension complied with the test recommended by the European Pharmacopoeia. The 1.0% hypromellose solution was found to be microbiologically stable for 6 months and physically stable for 12 months.

Enteral suspension of nifedipine for neonates. Part 2. Stability of an extemporaneously compounded nifedipine suspension.

OBJECTIVE: To investigate the chemical, microbiological and physical stability of an extemporaneously prepared nifedipine oral suspension, packaged in disposable syringes and prepared in a hospital pharmacy for paediatric use. METHODS: Two different suspensions were prepared, from nifedipine tablets and drug powder, by using an autoclaved 1.0% solution of hypromellose as the vehicle. The final theoretical drug concentration was 1 mg/mL. Doses of 1.0 ml were packaged into a 2 ml syringe with a cap. Nifedipine suspensions were stored under three conditions: at room temperature (22 degrees C), in a refrigerator (6 degrees C) protected from light, and at room temperature (22 degrees C) exposed to artificial daylight (400 lux) under controlled circumstances. The nifedipine concentration was measured in suspensions protected from light on days 0, 1, 3, 5, 7, 14, 21 and 28, and in suspensions exposed to light at 0, 3, 6, 18 and 24 h, and on days 2, 3, 5 and 7 after preparation. Nifedipine was analysed by a reproducible and validated stability-indicating HPLC-method. Microbiological and physical stability of the nifedipine suspension samples protected from light were examined for 28 days. RESULTS: Mean nifedipine concentration remained over 90% of the initial concentration throughout the 4-week study period in light-protected unit-dose suspensions, prepared from either crushed tablets or drug powder with hypromellose 1.0%. When exposed to light, however, nifedipine decomposed rapidly. Photodegradation of nifedipine exceeded 25% within 3 h and was essentially complete within 7 days. CONCLUSION: In the University Hospital of Kuopio, newborns have been treated with nifedipine suspension prepared from tablets, and preliminary experiences with administration of suspension have been encouraging. It may also be possible to apply this methodology to other medicines used in paediatrics.

Microbiological stability of a fentanyl, bupivacaine and clonidine mixture in a 0.9% sodium chloride infusion stored in syringes and reservoirs.

Combinations of extradural opioids and local anesthetic solutions are used in clinical practice, although little information exists on their microbiological or chemical stability. Currently there are no commercially available, prepacked, ready-to-use epidural mixtures of these medications and all mixtures must be prepared by the pharmacist. Epidural analgesic mixtures have been prepared on an as-needed basis. The aim of this study was to investigate the microbiological stability of a fentanyl, bupivacaine and clonidine mixture in a 0.9% sodium chloride infusion (without preservatives), prepared by the pharmacist in order to provide a basis for recommendations on the exchange of containgers (polypropylene syringes and polyvinylchloride [PVC] reservoirs). This mixture maintained microbiological stability for at least 28 days when prepared under aseptic conditions using a laminar air flow station, with a grade A environment and a B background, and using sterile clothes and equipment. During aseptic preparation in a grade A environment, less than 1 colony forming unit (CFU)/m3 and less than 3500 particles greater than 0.5 micrometers with no particle being greater than 5 micrometers, and in a grade B environment less than 10 CFU/m3 and less than 350,000 particles greater than 0.5 micrometers and less than 2,000 particles greater than 5 micrometers are allowed. Putatuive in situ antimicrobial activity of the drug mixture did not interfere with sterility testing. A pH difference was observed over time between the polypropylene syringes and the PVC reservoirs.

Stability of buprenorphine, haloperidol and glycopyrrolate mixture in a 0.9% sodium chloride solution.

Combinations of opioids and adjuvant drug solutions are often used in clinical practice while little information is available on their microbiological or chemical stability. Currently there are no commercially available, prepacked, ready-to-use epidural or subcutaneous mixtures. Thus, epidural and subcutaneous analgesic mixtures must be prepared in the pharmacy on an as-needed basis. Such mixtures are typically used for the treatment of severe pain in cancer patients. The aim of this study was to investigate the microbiological and chemical stability of a buprenorphine, haloperidol and glycopyrrolate mixture in a 0.9% sodium chloride solution. A high performance liquid chromatographic (HPLC) method and pH-meter were used to conduct the analyses. Antimicrobial activity of each component was studied by an agar dilution method. According to the results from the chemical and microbiological stability studies, this mixture can be stored in polypropylene (PP) syringes and polyvinyl chloride (PVC) medication cassettes for at least 30 days at either 21 degrees C or 4 degrees C, and for 16 days in PP syringes at 36 degrees C, and for 9 days in PVC medication cassettes at 36 degrees C.

Stability of Sufentanil in a Syringe Pump under Simulated Epidural Infusion.

Sufentanil is a potent micro-opioid and centrally acting analgesic. In the management of acute postoperative pain, sufentanil is often administered epidurally using a standard syringe pump. For epidural administration, sufentanil is diluted to a concentration of 1 to 2 micrograms/mL with 0.9% sodium chloride injection. The stability of sufentanil in a syringe pump under simulated epidural infusion was studied using a stability-indicating high-performance liquid chromatography method. The concentration of sufentanil was determined in polypropylene syringes connected with a polyethlyene or polyvinyl chloride (PVC) tubing, filter and epidural catheter. Sufentanil concentrations remained constant in polypropylene syringes connected to epidural catheters and in the whole epidural infusion system using polyethylene tubing. Sufentanil concentrations decreased 7% to 15% in syringes connected to PVC tubing, polyethylene tubing and the whole epidural infusion system using PVC tubing. Adsorption of 17% of the sufentanil onto an epidural filter occurred during the first hour of the infusion; thereafter, sufentanil concentration remained stable at levels that were 5% to 15% below the theoretical concentration. In conclusion, adsorption of sufentanil should be considered when a new filter and tubing of different materials are used.

Analysis of tropane alkaloids with thermospray high-performance liquid chromatography-mass spectrometry.

A thermospray high-performance liquid chromatography-mass spectrometry method for analysis of hyoscyamine and scopolamine in plant cell culture samples is described. The alkaloids were separated on a polymeric reversed-phase column with an alkaline ammonium acetate buffer-acetonitrile eluent. Selected-ion recording of the protonated molecular ions was used for quantitation of the compounds. The compounds were fragmented by discharge-assisted ionization and elevated thermospray capillary temperatures or ion repeller potentials.

Identification of indole alkaloids of Catharanthus roseus with liquid chromatography/mass spectrometry using collision-induced dissociation with the thermospray ion repeller.

Fragmentation of protonated molecular ions produced from catharanthine, tabersonine, ajmalicine and serpentine in a high-performance liquid chromatography (HPLC) thermospray ion source was studied. Collision-induced dissociation (CID) of the compounds was achieved by merely increasing the repeller potential; i.e. no discharge current was applied and filament was not on. Proportion of fragments to the protonated molecular ions increased with the potential at the 180-350 V range studied, but overall yield of detected ions decreased at the higher voltages in all cases. Comparison of fragments produced in the thermospray CID with those derived from the protonated molecular ions by colliding with argon in a triple-stage quadrupole instrument showed that the fragmentation is very similar in both cases. An analytical application for identifying the alkaloids from plant cell culture material by HPLC/mass spectrometry using the thermospray CID is described.

Isolation of Catharanthus alkaloids by solid-phase extraction and semipreparative HPLC.

A combination of moderate-pressure chromatography on C18 sorbent and preparative HPLC is developed for rapid isolation of alkaloids from Catharanthus roseus. The procedure is optimized for vindoline and catharanthine with respective yields of 3 and 2 mg per 1 g of dried leaves of the plant. The methodology is also applied for identification of the above and other alkaloids from cultured plant cells.

Electrochemical detection of indole alkaloids of Catharanthus roseus in high-performance liquid chromatography.

Hydrodynamic voltammograms for indole and five indole alkaloids with different amino functions were obtained in order to evaluate the applicability of high-performance liquid chromatography (HPLC) with coulometric detection to these compounds. With the exception of serpentine, which has a quaternary nitrogen in its structure, all the compounds were oxidised and gave net signals of greater than 25 nA pmol(-1) at potentials of between +0.2 and +0.85 V versus a solid Pd electrode in an acetate-buffered (pH 6.5) water-methanol-acetonitrile system. An HPLC assay for quantifying picomole amounts of catharanthine and ajmalicine in Catharanthus roseus cell culture samples is described.

Mass Spectral Evidence of the Occurrence of Vindoline in Heterotrophic Cultures of Catharanthus roseus Cells.

Vindoline concentrations in the leaves of 70 CATHARANTHUS ROSEUS of 3 cultivars were analyzed by HPLC, and 3 plants were selected for starting callus cultures on different media. When the initial calli were analyzed using a vindoline-specific RIA, the assay suggested a vindoline content of about 10 (-5)% dry weight for one-third of the first 60 cultures examined. Due to the unexpectedly high incidence of vindoline-positive calli, the screening programme was discontinued and efforts were concentrated on verifying the existence of this alkaloid in the cells. Suspension cultures derived from the 5 most immunopositive calli in an alkaloid production medium were analyzed by HPLC and GC/MS. Comparison with reference material showed that the heterotrophic suspension cultures contained a compound identical to vindoline.