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.