Magnocaine: Physical Compatibility and Chemical Stability of Magnesium Sulphate and Lidocaine Hydrochloride in Prefilled Syringes.

OBJECTIVE: To evaluate the physical compatibility and chemical stability of mixtures of magnesium sulphate and lidocaine in order to determine the feasibility of manufacturing a prefilled syringe combining these two drugs for use as an intramuscular (IM) loading dose for eclampsia prevention and/or treatment. This ready-to-use mixture will provide a more tolerable and accessible route of administration appropriate for widespread use. METHODS: Physical compatibility (pH, colour, and formation of precipitate) and chemical stability (maintaining > 90% of initial concentrations) of mixtures of MgSO4, using both commercially available MgSO4 (50%) and MgSO4 reconstituted from salt (61%), with lidocaine hydrochloride (2%) were evaluated every 14 days over six months. The concentration of lidocaine was determined by a stability indicating high performance liquid chromatographic method, while the concentration of magnesium was determined by an automated chemistry analyzer. RESULTS: No changes in pH, color or precipitates were observed for up to 6 months. The 95% confidence interval of the slope of the curve relating concentration to time, determined by linear regression, indicated that only the admixtures of commercially-available magnesium sulfate and lidocaine as well as the 61% magnesium sulfate solution (reconstituted from salt) maintained at least 90% of the initial concentration of both drugs at 25°C and 40°C at 6 months. CONCLUSIONS: Commercially available MgSO4 and lidocaine hydrochloride, when combined, are stable in a pre-filled syringe for at least six months in high heat and humidity conditions. This finding represents the first step in improving the administration of magnesium sulphate in the treatment and prevention of eclampsia in under-resourced settings.

Stability of Dabigatran Etexilate in Manufacturer's Blister Pack, Unit-Dose Packaging, and Community Pharmacy Blister Pack.

BACKGROUND: Dabigatran, a direct thrombin inhibitor, is indicated for the prevention and treatment of venous thromboembolism and for stroke prophylaxis in atrial fibrillation. The manufacturer recommends that dabigatran etexilate be retained in the original packaging until administration. Currently, no information exists about the stability of dabigatran etexilate outside its original packaging. OBJECTIVE: To evaluate the stability of dabigatran etexilate capsules over 120 days, with storage in the manufacturer's original packaging, in unit-dose packaging, and in community pharmacy blister packaging. METHODS: Commercially available dabigatran etexilate capsules (110 mg) were stored at room temperature (25°C) in the manufacturer's original blister pack, in unit-dose packaging, or in community pharmacy blister packs. Samples were collected from each container daily for the first 3 days, weekly up to 28 days, every other week until day 98, and at day 120. Suspensions were prepared, pH was evaluated, and samples were stored at -85°C until analysis. Each sample was analyzed in duplicate by a validated, stability-indicating high-performance liquid chromatography - ultraviolet detection method. The capsules were considered stable if they maintained at least 90% of the initial concentration. RESULTS: Dabigatran etexilate capsules maintained 100.4% of the original concentration with 120 days of storage in the manufacturer's original blister pack, 98.7% with storage in unit-dose packaging, and 98.0% with storage in community pharmacy blister packs. There were no notable changes in appearance, ease of suspension of the capsule content, or pH over the 120-day period. CONCLUSION: Dabigatran etexilate 110-mg capsules were stable for 120 days with storage at room temperature in 3 types of packaging widely used in hospital and community settings.

CONTEXTE: Le dabigatran, un inhibiteur direct de la thrombine, est approuvé pour la prévention et le traitement des événements thromboemboliques veineux et pour la prophylaxie de l'accident vasculaire cérébral en présence de fibrillation auriculaire. Le fabricant recommande que le dabigatran etexilate soit gardé dans le conditionnement d'origine jusqu'à l'administration. Il n'existe aucune donnée sur la stabilité du dabigatran etexilate hors du conditionnement d'origine. OBJECTIF: Évaluer la stabilité de capsules de dabigatran etexilate sur une période de 120 jours lorsqu'elles sont entreposées dans : le conditionnement d'origine du fabricant, un conditionnement unitaire ou un pilulier de type plaquette alvéolée préparé en pharmacie communautaire. MÉTHODES: Des capsules de 110 mg de dabigatran etexilate, disponibles sur le marché, ont été entreposées à température ambiante (25 °C) soit dans la plaquette alvéolée d'origine du fabricant, soit dans un conditionnement unitaire, soit dans un pilulier de type plaquette alvéolée préparé en pharmacie communautaire. Des échantillons ont été prélevés de chaque type d'emballage : quotidiennement pour les 3 premiers jours, hebdomadairement pour les 28 jours suivants, puis toutes les deux semaines jusqu'au jour 98, et au jour 120. Des suspensions ont été préparées, le pH mesuré et les échantillons entreposés à −85 °C jusqu'à l'analyse. Chaque échantillon a été soumis à une double analyse à l'aide d'une épreuve validée mesurant la stabilité par chromatographie liquide haute performance avec détection ultraviolette. Les capsules étaient considérées comme stables si elles conservaient au moins 90 % de leur concentration initiale. RÉSULTATS: Au bout des 120 jours, les capsules de dabigatran etexilate ont conservé 100,4 % de leur concentration de départ lorsqu'entreposées dans les plaquettes alvéolées d'origine du fabricant, 98,7 % lorsqu'entreposées dans un conditionnement unitaire et 98,0 % lorsqu'entreposées dans un pilulier de type plaquette alvéolée préparé en pharmacie communautaire. Aucun changement notable de l'apparence, du pH et de la facilité de la mise en suspension du contenu de la capsule n'a été observé pendant la période de 120 jours. CONCLUSION: Les capsules de 110 mg de dabigatran etexilate sont demeurées stables pendant la période de 120 jours d'entreposage à température ambiante dans trois types de conditionnement largement utilisés dans les hôpitaux et les pharmacies communautaires.

Stability of extemporaneously compounded dexamethasone in glass and plastic bottles and plastic syringes.

BACKGROUND: Dexamethasone is widely used to treat rheumatic and endocrine disorders and chemotherapy-induced nausea and vomiting. A palatable, alcohol-free liquid formulation, with a suitable concentration to allow reasonable administration volume, is available only via extemporaneous compounding. OBJECTIVE: To evaluate the stability of dexamethasone suspensions in commercially available vehicles (Oral Mix and Oral Mix SF) in various types of containers after storage at 25°C and 4°C for up to 91 days. METHODS: Dexamethasone suspensions (1 mg/mL) were prepared in Oral Mix and Oral Mix SF and then transferred to amber glass and plastic prescription bottles and plastic oral syringes. Suspensions in all 3 types of containers were stored at 25°C; suspensions in glass and plastic bottles were also stored at 4°C. Samples were collected weekly from each container up to 28 days and then every 2 weeks up to 91 days. The samples were analyzed by a validated, stability-indicating high-performance liquid chromatography - ultraviolet detection method. A suspension was considered stable if it maintained at least 90% of its initial dexamethasone concentration. Changes in colour, taste, odour, precipitation (and ease of resuspension), and pH were used to assess physical compatibility. RESULTS: All suspensions maintained at least 96% of the original concentration for up to 91 days with storage at 25°C or at 4°C. No notable changes in colour, taste, odour, precipitation, or pH were observed over the 91-day period. CONCLUSION: Dexamethasone suspensions (1 mg/mL) in Oral Mix and Oral Mix SF, stored in amber glass or plastic bottles or plastic syringes at 25°C or in amber glass or plastic bottles at 4°C can be expected to remain stable for up to 91 days.

CONTEXTE: La dexaméthasone est couramment utilisée pour traiter les affections endocriniennes et rhumatismales ainsi que les nausées et vomissements causés par la chimiothérapie. Mais, une forme liquide sans alcool, au goût acceptable et d'une concentration suffisante pour permettre l'administration d'un volume acceptable de médicament ne peut être obtenue que par la réalisation d'une préparation extemporanée. OBJECTIF: Évaluer la stabilité de suspensions de dexaméthasone préparées dans des excipients disponibles sur le marché (Oral Mix et Oral Mix SF) et placées dans différents types de contenant après leur entreposage à 4 °C et à 25 °C pendant une période allant jusqu'à 91 jours. MÉTHODES: Des suspensions de dexaméthasone (1 mg/mL) ont été préparées dans des excipients Oral Mix et Oral Mix SF, puis transférées dans des seringues orales de plastique ambré et dans des flacons pour médicaments d'ordonnance en plastique et en verre ambrés. Des suspensions contenues dans les trois types de contenant ont été entreposées à 25 °C, alors que seules des préparations contenues dans des flacons de verre et de plastique ont aussi été entreposées à 4 °C. Des échantillons ont été prélevés de chaque contenant une fois par semaine jusqu'à 28 jours, puis toutes les deux semaines jusqu'à 91 jours. Les échantillons ont été analysés à l'aide d'une épreuve validée mesurant la stabilité par chromatographie liquide haute performance avec détection ultraviolette. Une suspension était jugée stable si elle conservait au moins 90 % de sa concentration initiale de dexaméthasone. Tout changement dans la couleur, le goût, l'odeur, le pH ainsi que la formation de précipité (et la facilité de remise en suspension) a servi à l'évaluation de la compatibilité physique. RÉSULTATS: Toutes les suspensions ont conservé au moins 96 % de leur concentration initiale pendant une période allant jusqu'à 91 jours dans des conditions d'entreposage de 25 °C ou de 4 °C. Aucun changement notable de couleur, de goût, d'odeur, de formation de précipité ou de pH n'a été observé pendant la période de 91 jours. CONCLUSION: Les préparations de dexaméthasone en suspension (1 mg/mL) dans les bases Oral Mix et Oral Mix SF conservées dans des seringues de plastique ambré ou dans des flacons pour médicaments d'ordonnance en plastique ou en verre ambrés à 25 °C ainsi que celles conservées dans des flacons pour médicaments d'ordonnance en plastique ou en verre ambrés à 4 °C devraient demeurer stables pendant une période allant jusqu'à 91 jours. [Traduction par l'éditeur].

Stability of epinephrine at standard concentrations.

BACKGROUND: To minimize medication errors, standard concentrations are recommended for medications intended for continuous infusion in pediatric patients. Premixing of epinephrine (commonly used to manage septic shock in children) would improve timeliness, safety, and cost-effectiveness. However, information about the stability of epinephrine at standard concentrations is limited. OBJECTIVES: To evaluate the stability of epinephrine in 5% dextrose in water at standard concentrations and to extend its expiration date after storage in infusion bags at 4°C and 25°C for up to 30 days. METHODS: A total of 6 infusion bags were prepared with 200 mL of epinephrine solution, 2 bags for each of 3 standard concentrations (25, 50, and 100 µg/mL). Three bags (one for each concentration) were stored under refrigeration (4°C), and the remaining 3 bags were stored at room temperature (25°C). Physical characteristics (including pH, colour, and presence of precipitate) were evaluated daily for the first 14 days and every 1 to 5 days thereafter until day 30. Three 1.5-mL samples were collected from each bag immediately after preparation (time 0), every 24 h (at 24 h, 48 h, 72 h, 96 h, etc.) for the first 14 days, and every 1 to 5 days thereafter until day 30. Each sample was analyzed by stability-indicating high-performance liquid chromatography. A solution was considered stable if it maintained at least 90% of its initial concentration. RESULTS: No notable changes in pH, colour, or precipitation were observed in any of the solutions after storage at 4°C or 25°C for up to 30 days. All formulations maintained more than 95% of the initial epinephrine concentration on day 30. In addition, the calculated lower limit of the 95% confidence interval indicated that 93% or more of the initial concentration remained on day 30. CONCLUSIONS: Preparations of epinephrine were stable for up to 30 days, with or without refrigeration. Because stability alone does not guarantee bioavailability or efficacy of a drug, future clinical studies are recommended to evaluate the pharmacokinetics and pharmacodynamics of these formulations.

CONTEXTE: Afin de réduire au maximum les erreurs de médication, il est recommandé d'utiliser des concentrations standards pour les médicaments administrés par perfusion continue aux enfants. La préparation préalable des solutions d'épinéphrine (couramment utilisée pour traiter le choc septique chez l'enfant) permettrait d'améliorer la rapidité d'action, la sécurité et le rapport coût-efficacité. Il existe malheureusement peu de données portant sur la stabilité de solutions d'épinéphrine de concentrations standards. OBJECTIFS: Évaluer la stabilité de l'épinéphrine de concentrations standards dans du dextrose à 5 % dans l'eau et augmenter la durée de conservation des solutions entreposées dans des sacs pour perfusion à 4 °C et à 25 °C jusqu'à 30 jours. MÉTHODES: Six sacs pour perfusion contenant 200 mL d'une solution d'épinéphrine ont été préparés, soit une paire de chacune des trois concentrations standards (25, 50 et 100 µg/mL). Trois sacs ont été conservés au réfrigérateur (4 °C) et les trois autres ont été entreposés à la température ambiante (25 °C). Les propriétés physiques (notamment le pH, la couleur et la présence de précipité) ont été évaluées quotidiennement les 14 premiers jours, puis à des intervalles de 1 à 5 jours jusqu'au jour 30. Trois échantillons de 1,5 mL ont été recueillis de chaque sac immédiatement après la préparation de la solution (temps 0), puis toutes les 24 heures (24 h, 48 h, 72 h, 96 h, etc.) pendant les 14 premiers jours et ensuite à des intervalles de 1 à 5 jours jusqu'à la fin de la période de 30 jours. Chaque échantillon a été analysé à l'aide d'une épreuve mesurant la stabilité par chromatographie liquide haute performance. Une solution était considérée comme stable si elle conservait au moins 90 % de sa concentration initiale. RÉSULTATS: Aucun précipité et aucun changement notable du pH ou de la couleur n'ont été observés dans l'ensemble des solutions après un entreposage à 4 °C ou à 25 °C d'une période de 30 jours. Toutes les préparations avaient conservé plus de 95 % des concentrations initiales d'épinéphrine au jour 30. De plus, la limite inférieure de l'intervalle de confiance à 95 % indiquait que les préparations avaient conservé 93 % ou plus de leurs concentrations initiales au jour 30. CONCLUSIONS: Les préparations d'épinéphrine sont demeurées stables pendant les 30 jours, qu'elles aient été réfrigérées ou non. Comme la stabilité seule ne garantit pas la biodisponibilité ou l'efficacité d'un médicament, d'autres études cliniques sont recommandées afin d'évaluer le comportement pharmacocinétique et pharmacodynamique de ces préparations. [Traduction par l'éditeur].

Stability of clonidine suspension in oral plastic syringes.

PURPOSE: The stability of clonidine suspensions stored at room temperature and under refrigeration for three months was evaluated. METHODS: Oral suspensions of clonidine 0.01 mg/mL were prepared in Ora-Blend and stored in clear plastic syringes at 25 °C and 4 °C. Samples were collected from each syringe at the time of preparation, at weekly intervals for up to 28 days, and on days 42, 56, 77, and 91. Changes in color, taste, and pH, as well as visual evidence of precipitation, were used to determine physical compatibility. Immediately after the physical observations were made, 1.5-mL samples from each syringe were transferred to polypropylene freezer vials and stored at -85 °C until high-performance liquid chromatographic (HPLC) analysis. The samples were analyzed by a validated stability-indicating HPLC-ultraviolet-light detection method. Stability was defined as the retention of at least 90% of the initial clonidine concentration. The precision of the assay was evaluated by intraday and interday validation methods. RESULTS: Clonidine suspensions stored at 25 °C and 4 °C maintained 99.2% and 99.0% of the initial concentration for 91 days, respectively. No interfering peaks were generated by forced degradation of clonidine with heat, hydrochloric acid, sodium hydroxide, or hydrogen peroxide There were no notable changes in pH, and all samples remained physically unchanged during the study period. CONCLUSION: An extemporaneously prepared suspension of clonidine 0.01 mg/mL in Ora-Blend was stable for at least 91 days when stored in clear plastic syringes at either 25 °C or 4 °C.

Compatibility and stability of morphine sulphate and naloxone hydrochloride in 0.9% sodium chloride for injection.

BACKGROUND: Naloxone may be administered in conjunction with morphine to reduce the risk of opioid-induced pruritis. Combining these drugs for coadministration may be beneficial, but little is known about their physical compatibility and stability in combined solutions. OBJECTIVE: To describe the physical compatibility and stability of morphine sulphate and naloxone hydrochloride (at various concentrations) in IV admixtures. METHODS: The physical compatibility and stability of admixtures of morphine 1000 µg/mL and naloxone 4 µg/mL, 12.5 µg/mL, and 25 µg/mL in 0.9% sodium chloride were studied. For each concentration of naloxone, one bag was stored at room temperature (22°C) for 72 h and one bag was stored under refrigeration (4°C) for 30 days. For all preparations, physical characteristics, including pH, colour, and formation of precipitate, were evaluated. The samples were also analyzed by a stability-indicating high-performance liquid chromatographic method. Stability was defined as the retention of at least 90% of the initial concentration. RESULTS: No notable changes in pH or colour and no macroprecipitation were observed in any of the preparations after storage at 22°C for up to 72 h or at 4°C for up to 30 days. All preparations maintained more than 90% of the initial concentrations of morphine and naloxone at the end of the respective study periods. The calculated lower limit of the 95% confidence interval also indicated that 90% or more of the initial concentration remained at the end of each study period. CONCLUSION: Admixtures of morphine sulphate and naloxone hydrochloride were stable for 72 h at room temperature and for 30 days with refrigeration.

CONTEXTE: La naloxone peut être administrée en concomitance avec la morphine pour réduire le risque de prurit induit par les opioïdes. L'association de ces médicaments pour leur administration concomitante peut être bénéfique, mais on ne sait que peu de choses sur leur compatibilité physique et leur stabilité dans des solutions combinées. OBJECTIF: Décrire la compatibilité physique et la stabilité du sulfate de morphine et du chlorhydrate de naloxone (à diverses concentrations) mélangés dans des solutions pour administration i.v. MÉTHODES: La compatibilité physique et la stabilité des mélanges de morphine à 1000 µg/mL et de naloxone à 4 µg/mL, 12,5 µg/mL et 25 µg/mL dans du chlorure de sodium à 0,9 % ont été étudiées. Pour chaque concentration de naloxone, on a entreposé un sac à la température ambiante (22 °C) pendant 72 heures et un autre au réfrigérateur (4 °C) pendant 30 jours. Les propriétés physiques, notamment le pH, la couleur et la formation de précipité, ont été évaluées pour toutes les préparations. Les échantillons ont aussi été analysés à l'aide d'une épreuve validée mesurant la stabilité par chromatographie liquide haute performance. La stabilité a été définie comme étant la rétention d'au moins 90 % de la concentration initiale des agents. RÉSULTATS: Aucun changement notable du pH ou de la couleur et aucune formation de macroprécipité n'ont été observés dans l'ensemble des préparations qui ont été conservées à une température de 22 °C pendant un maximum de 72 heures ou à une température de 4 °C pendant un maximum de 30 jours. Toutes les préparations ont conservé plus de 90 % de leurs concentrations initiales de morphine et de naloxone à la fin de leurs périodes d'étude respectives. La limite inférieure de l'intervalle de confiance à 95 % indiquait également que 90 % ou plus de la concentration initiale subsistait à la fin de chaque période d'étude. CONCLUSION: Les mélanges de sulfate de morphine et de chlorhydrate de naloxone sont demeurés stables pendant 72 heures à la température ambiante et pendant 30 jours lorsqu'ils étaient réfrigérés. [Traduction par l'éditeur].

Stability of propranolol in extemporaneously compounded suspensions.

BACKGROUND: Propranolol is a drug of choice for many diseases occurring in neonates and infants, an age group for which oral suspensions are required almost exclusively. Many adult and elderly patients for whom propranolol is prescribed are also unable to swallow solid dosage forms. In Canada, propranolol is not commercially available in a liquid dosage form, and existing recipes for extemporaneously compounded suspensions of propranolol (1 mg/mL) are limited by concerns regarding diabetes mellitus in certain subpopulations, the need for a more concentrated suspension for patients taking larger doses, and the tediousness of compounding. OBJECTIVE: To evaluate the stability of propranolol suspensions in a sugar-free, commercially available vehicle after storage at room temperature and under refrigeration for up to 120 days. METHODS: Suspensions of propranolol (2 and 5 mg/mL) were prepared in the sugar-free vehicle (Ora-Blend SF), placed in 100-mL amber plastic prescription bottles, and stored at 25°C and 4°C. Samples were collected from each bottle once weekly for 120 days, stored frozen, and analyzed by a validated, stability-indicating high-performance liquid chromatography - ultraviolet detection method. A suspension was considered stable if it maintained at least 90% of its initial concentration of propranolol. Physical compatibility was evaluated in terms of colour, taste, precipitation, and pH. RESULTS: Propranolol suspensions 2 mg/mL and 5 mg/mL stored at 25°C maintained at least 94.7% of their initial concentration for 120 days, and suspensions stored at 4°C maintained at least 93.9% of their initial concentration for 120 days. There were no notable changes in pH, and all samples remained physically unchanged except for a slight change in colour, around day 70, of suspensions stored at room temperature. CONCLUSION: Propranolol suspensions (2 mg/mL and 5 mg/mL) prepared in Ora-Blend SF and stored in plastic prescription bottles at either 25°C or 4°C are expected to remain stable for 120 days.

CONTEXTE: Le propranolol est un médicament de choix pour de nombreuses maladies des nouveau-nés et des nourrissons, un groupe d'âge pour lequel les suspensions orales sont presque toujours requises. De nombreux patients adultes et âgés à qui l'on prescrit du propranolol sont également incapables d'avaler des formes pharmaceutiques solides. Au Canada, le propranolol n'est pas commercialisé sous forme liquide et les recettes actuelles pour les préparations extemporanées de ce médicament en suspension (1 mg/mL) sont limitées par des inquiétudes touchant le diabète sucré chez certaines sous-populations, le besoin d'une suspension plus concentrée chez les patients prenant de plus fortes doses et le long travail que nécessitent de telles préparations. OBJECTIF: Évaluer la stabilité de suspensions de propranolol préparées dans un excipient sans sucre disponible dans le commerce, conservées à la température ambiante et au réfrigérateur pendant un maximum de 120 jours. MÉTHODES: Des suspensions de propranolol (2 mg/mL et 5 mg/mL) ont été préparées dans un excipient sans sucre (Ora-Blend SF) et conditionnées dans des flacons pour médicaments d'ordonnance en plastique ambré de 100 mL, puis entreposées à une température de 25 °C ou de 4 °C. Des échantillons ont été prélevés de chaque flacon une fois par semaine pendant 120 jours, conservés au congélateur et analysés à l'aide d'une épreuve validée mesurant la stabilité par chromatographie liquide haute performance avec détection ultraviolette. La suspension était considérée comme stable si elle conservait au moins 90 % de la concentration initiale de propranolol. La compatibilité physique a été évaluée en contrôlant tout changement dans la couleur, le goût ou le pH et toute formation de précipité. RÉSULTATS: Les suspensions de propranolol à 2 mg/mL et à 5 mg/mL entreposées à une température de 25 °C ont conservé au moins 94,7 % de la concentration initiale de propranolol pendant 120 jours et les suspensions entreposées à une température de 4 °C ont conservé au moins 93,9 % de la concentration initiale de propranolol pendant 120 jours. On n'a observé aucun changement notable du pH et tous les échantillons ont conservé leurs propriétés physiques, à l'exception d'un léger changement de couleur, vers le 70e jour, pour les suspensions entreposées à la température ambiante. CONCLUSION: Les suspensions de propranolol (2 mg/mL et 5 mg/mL) préparées dans un excipient d'Ora-Blend SF, puis conditionnées dans des flacons pour médicaments d'ordonnance en plastique et entreposées à une température de 25 °C ou de 4 °C devraient demeurer stables pendant 120 jours. [Traduction par l'éditeur].

Stability of levetiracetam in extemporaneously compounded suspensions.

BACKGROUND: Levetiracetam is widely used as adjunctive therapy in the treatment of partial-onset seizures, myoclonic seizures, primary generalized tonic-clonic seizures, and idiopathic generalized epilepsy in the community and in hospital. However, no convenient, easy-to-swallow dosage form is commercially available in Canada. Moreover, no stability data are available for this antiepileptic prepared in a vehicle combining Ora-Sweet sweetener and Ora-Plus suspending agent. OBJECTIVE: To evaluate the stability of levetiracetam suspensions in amber plastic bottles at room temperature and under refrigeration for up to 91 days. METHODS: Suspensions of levetiracetam (50 mg/mL) were prepared in a 1:1 mixture of Ora-Sweet sweetening agent and Ora-Plus suspending agent. The suspensions were transferred to 50-mL amber plastic prescription bottles, which were stored at 25°C or at 4°C. Samples were collected from each bottle at time zero and on days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, and 91. The samples were analyzed in triplicate by a validated, stability-indicating high-performance liquid chromatography method with ultraviolet detection. A suspension was considered stable if it maintained at least 90% of its initial concentration of levetiracetam. Colour, odour, taste, clarity, and pH were assessed to determine physical compatibility. RESULTS: All samples remained physically unchanged over time, and there was no significant change in pH. The 95% confidence interval of the slope of the curve relating concentration to time, determined by linear regression, indicated that suspensions stored at 25°C would maintain at least 91.4% of the initial levetiracetam concentration for 91 days and that suspensions stored at 4°C would maintain at least 93.2% of the initial concentration for 91 days, with 95% confidence. CONCLUSION: Levetiracetam suspensions prepared in Ora-Sweet/Ora-Plus vehicle and stored in plastic prescription bottles at either 25°C or 4°C can be expected to remain stable for 91 days.

Stability of Vancomycin 25 mg/mL in Ora-Sweet and Water in Unit-Dose Cups and Plastic Bottles at 4°C and 25°C.

BACKGROUND: Solutions of vancomycin for oral administration are not available commercially in Canada or the United States but are needed for patients who cannot swallow capsules. OBJECTIVE: To evaluate the stability of vancomycin solutions stored in unit-dose cups and plastic bottles under refrigeration (4°C) and at room temperature (25°C) for up to 75 days. METHODS: Vancomycin 25 mg/mL in Ora-Sweet vehicle and water (1:1 ratio by volume) was dispensed into opaque blue polyethylene unit-dose cups with aluminum seal (14 replicates) or amber plastic prescription bottles (6 replicates). Seven cups and 3 bottles were refrigerated (4°C), and the remainder of the containers were stored at room temperature (25°C). At the time of preparation and at 15, 30, 40, 50, 63, and 75 days, 3 aliquots were collected from one of the cups and from every bottle and were stored frozen (-85°C) until the time of analysis. Physical characteristics were evaluated at each time point, including measurement of pH and visual assessment of colour and precipitation. After thawing, the samples were analyzed in triplicate by a validated stability-indicating high-performance liquid chromatography method. A solution was considered stable if 90% of the initial concentration of vancomycin was maintained. RESULTS: No notable changes in colour, taste, or pH were observed in vancomycin solutions stored in the unit-dose cups at 4°C or 25°C or in the plastic bottles stored at 4°C over the 75-day study period. Starting on day 63, a white precipitate was observed in the solutions stored in plastic bottles at 25°C, but there were no notable changes in taste or pH during the 75-day period. The 95% confidence interval of the slope of the curve relating concentration to time, determined by linear regression, indicated that vancomycin solutions stored in cups or bottles at 4°C would maintain at least 93.6% of the initial vancomycin concentration for 75 days and that solutions stored at 25°C would maintain at least 90.0% of the initial concentration for 30 days (cups) or 26 days (bottles), with 95% confidence. CONCLUSIONS: Vancomycin 25 mg/mL stored in unit-dose cups or plastic bottles at 4°C was stable for at least 75 days, whereas solutions stored in cups or bottles at 25°C are expected to be stable for 30 or 26 days, respectively.

Stability of Levothyroxine in Sodium Chloride for IV Administration.

BACKGROUND: Levothyroxine by IV administration is often prescribed in the intensive care unit for the management of potential solid organ donors, following declaration of brain death and provision of consent for organ donation. Published data on the stability of levothyroxine in IV solutions are limited. OBJECTIVE: To evaluate the physical compatibility and chemical stability, over a 24-h period, of 2 concentrations of levothyroxine in 0.9% sodium chloride with storage at room temperature and with exposure to or protection from light. METHODS: Levothyroxine solutions (0.4 µg/mL and 2.0 µg/mL) were prepared in 50-mL minibags of 0.9% NaCl and stored at room temperature (25°C) with exposure to or protection from light. Samples were collected from each minibag at time 0 and after 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 8.0, 12.0, and 24.0 h. The samples were analyzed in triplicate with a validated stability-indicating high-performance liquid chromatography method using ultraviolet detection. A solution was considered stable if it maintained 90% of its initial concentration of levothyroxine. Changes in colour, clarity, and pH were assessed to determine the physical compatibility of the solutions. RESULTS: All samples remained clear, colourless, and free of precipitate throughout the study, and there were no significant changes in pH. Based on the 95% confidence interval of the slope of the curve relating concentration to time determined by linear regression, solutions of levothyroxine with concentration 0.4 µg/mL would maintain at least 90% of the initial concentration for 16.9 h with exposure to light and for 18.0 h if kept in the dark. Solutions of levothyroxine with concentration 2.0 µg/mL would maintain at least 90% of the initial concentration for 6.5 h with exposure to light and for 12.0 h if kept in the dark, with 95% confidence. CONCLUSIONS: Extemporaneously prepared solutions of levothyroxine in 0.9% NaCl can be expected to remain stable for at least 6.5 h if stored without protection from light and at least 12 h if stored in the dark. Stability is related to concentration, with more dilute solutions having greater stability.

Stability of Hydromorphone-Ketamine Solutions in Glass Bottles, Plastic Syringes, and IV Bags for Pediatric Use.

OBJECTIVES: To evaluate the stability of mixtures of hydromorphone and ketamine in 0.9% sodium chloride (normal saline [NS]) after storage for up to 7 days at room temperature (25°C). METHODS: The stability of 3 standard mixtures of hydromorphone and ketamine (hydromorphone 0.2 mg/mL + ketamine 0.2 mg/mL, hydromorphone 0.2 mg/mL + ketamine 0.6 mg/mL, and hydromorphone 0.2 mg/mL + ketamine 1.0 mg/mL) in NS was studied. Portions of each mixture were transferred to 3 brown glass bottles (100 mL), 3 plastic syringes (50 mL), and 3 IV bags (50 mL), which were then stored at room temperature (25°C). Physical characteristics, including pH, colour, and precipitation, were evaluated daily. Three 1.5-mL samples were collected from each bottle, syringe, and IV bag at baseline, at 24, 48, and 72 hours, and on day 7. Samples were analyzed in triplicate by a stability-indicating high-performance liquid chromatography method. Solutions were considered stable if they maintained 90% of the initial concentration of each drug. Samples from syringes and IV bags were subjected to standard sterility testing by incubation for 5 days in an enriched culture media. RESULTS: No notable changes in pH or colour were observed, and no precipitation occurred in any of the solutions. All formulations maintained more than 90% of the initial concentration of each drug on day 7. No bacterial growth was observed in any of the samples tested. CONCLUSIONS: Mixtures of hydromorphone and ketamine were stable for up 7 days at 25°C, and the sterility of the preparations was maintained. Because stability alone does not guarantee efficacy, it is recommended that clinical studies be conducted to evaluate the pharmacokinetics and pharmacodynamics of these formulations.

Mycophenolate pharmacokinetics in early period following lung or heart transplantation.

BACKGROUND: The available pharmacokinetic and pharmacodynamic data on mycophenolic acid (MPA), the pharmacologically active metabolite of mycophenolate mofetil (MMF), are derived largely from renal transplant patients, not thoracic transplant recipients. OBJECTIVE: To evaluate, in a pilot study, the pharmacokinetics of MPA at 3 different times in the early period (up to the first 9 mo) following lung or heart transplantation. METHODS: Nine patients were entered into this open-label study. Upon administration of a steady-state morning MMF dose, blood samples were collected at 0, 20, 40, 60, and 90 minutes and at 2, 4, 6, 8, 10, and 12 hours after the dose at 3 times (denoted as sampling periods 1, 2, and 3) in the early posttransplant period. Total MPA concentrations were measured by a validated HPLC method with ultraviolet detection and followed by ultrafiltration of pooled samples for unbound MPA concentrations. Pharmacokinetic parameters (maximal concentration [C(max)], dose-normalized C(max), time to C(max), minimum concentration, predose concentration, AUC, dose-normalized AUC, free fraction, free AUC) were calculated by traditional noncompartmental methods. RESULTS: Patient characteristics included 7 men and 2 women, 5 lung and 4 heart transplant recipients, mean +/- SD age 53 +/- 11 years, and weight 77 +/- 14 kg. All patients were receiving prednisone and cyclosporine (with the exception of 2 pts. on tacrolimus during sampling periods 2 and 3). Sampling periods 1, 2, and 3 occurred on posttransplant days 15 +/- 13, 56 +/- 33, and 125 +/- 73, respectively. No significant differences were found between sampling periods in any pharmacokinetic parameter. Drug exposure as evaluated by AUC was 39.95 +/- 44.86, 25.24 +/- 25.68, and 43.96 +/- 38.67 micro g*h/mL during sampling periods 1, 2, and 3, respectively, (p > 0.05). CONCLUSIONS: As of September 26, 2003, this is the first study to systematically evaluate MPA pharmacokinetics in thoracic transplant recipients at 3 different time points during the early posttransplant period. Wide interpatient variability in MPA pharmacokinetics was observed, thus emphasizing the need to individualize dosing of MMF and to further evaluate important pharmacokinetic/pharmacodynamic parameters and endpoints that impact on clinical outcomes. Further studies involving more patients and pharmacodynamic outcomes are underway to help identify optimal MMF strategies.

Pharmacokinetics and protein binding of mycophenolic acid in stable lung transplant recipients.

Mycophenolate mofetil (MMF) use is increasing in solid organ transplantation. Mycophenolic acid (MPA), the active metabolite of MMF, is highly protein bound and only free MPA is pharmacologically active. The average MPA free fraction in healthy adult individuals, stable renal transplant recipients, and heart transplant recipients is approximately 2 to 3%. However, no data are currently available on MPA protein binding in stable lung transplant recipients and little is known regarding MPA's pharmacokinetic characteristics after lung transplantation. The purpose of this study was to characterize the pharmacokinetic profile and protein binding of MPA in this patient population. Seven patients were entered into the study. On administration of a steady-state morning MMF dose, blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 8, 9, 10, and 12 hours post-dose. Total MPA concentrations were measured by a validated HPLC method with UV detection and followed by ultrafiltration of pooled samples for free MPA concentrations. Area under the curve (AUC), peak concentration (Cmax), time to peak concentration (Tmax), trough concentration (Cmin), free fraction (f), and free MPA AUC were calculated by traditional pharmacokinetic methods. Patient characteristics included; 3 males and 4 females, an average of 4.4 years post-lung transplant (range, 0.3-11.5 yr), mean (+/- SD) age of 50 +/- 10 years and weight 69 +/- 20 kg. Mean albumin concentration was 37 +/- 3 g/L and serum creatinine was 142 +/- 49 micromol/L. All patients were on cyclosporine and prednisone. MMF dosage ranged from 1 to 3 g daily (35.5 +/- 14.1 mg/kg/d; range, 15.2-60.0 mg/kg/d). Mean (+/- SD) AUC was 45.78 +/- 18.35 microg.h/mL (range, 16.56-74.22 microg.h/mL), Cmax was 17.37 +/- 7.69 microg/mL (range, 4.92-26.63 microg/mL), Tmax was 1.2 +/- 0.4 hours (range, 1.0-2.0 h), Cmin was 3.12 +/- 1.41 microg/mL (range, 1.47-4.82 microg/mL), f was 2.90 +/- 0.56% (range, 2.00-3.40%), and free MPA AUC was 1.29 +/- 0.50 microg.h/mL (range, 0.54-1.88 microg.h/mL). This is the first study to determine these pharmacokinetic characteristics of MPA in the lung transplant population. Further studies should focus on identification of MMF dosing strategies that optimize immunosuppressive efficacy and minimize toxicity in lung allograft recipients.