BACKGROUND AND RATIONALE:A clozapine oral suspension is not commercially available in Canada and is required for administration to patients who cannot swallow intact tablets. While a stable formula has been described, no studies document the effectiveness of the preservative system used in this formulation to control inadvertent microbial contamination by the user during use of the preparation. OBJECTIVE:The objective of this study was to evaluate the antimicrobial effectiveness of 25-mg/mL and 50-mg/mL oral suspension of clozapine after 120-days of storage at 20o-25oC, ensuring a compounded clozapine preparation can be provided to a patient with confidence and supporting the beyond-use-date of the preparation. METHODS:The USP Chapter <51> Preservative Effectiveness Test protocol was followed as described for category 3 products. After storage for 120-days at 20o-25oC in amber glycol-modified polyethylene terephthalate (PET-G), both the 25-mg/mL and 50-mg/mL clozapine suspensions were inoculated with 3 different strains of bacteria and 2 strains of fungi and incubated for 28-days. On days 7, 14 and 28, the bacterial and fungal colony counts determined the antimicrobial effectiveness of the suspension. The suitability of the microbial recovery method was validated prior to completing the challenge test. RESULTS:The microbial load of the clozapine suspensions declined from an initial CFU count between 105-106 to less than 10-CFU by day 7 for bacteria and less than 30-50 CFU for yeast & fungi. On days 14 and 28, the bacteria showed no changes from counts at day 7th, while the yeast & fungi declined to less than 10 CFU. This indicates effective antimicrobial activity of the clozapine oral suspension. CONCLUSIONS:The 25-mg/mL and 50-mg/mL clozapine suspensions have been demonstrated to effectively control bacterial and fungal contamination, as judged by the USP Chapter <51> Antimicrobial Effectiveness Test. This bracketed formulation has been previously demonstrated to retain more than 95% of its initial active concentration when stored at 4oC or 25oC for 120-days.

Studies have evaluated epinephrine stability in higher concentrations and shorter durations than we require. The objective of this study was to evaluate the chemical stability of epinephrine in syringes at concentrations of 10 mcg/mL in 0.9% sodium chloride at 4°C and 25°C. Solutions of 10 mcg/mL epinephrine in 0.9% sodium chloride were prepared and stored in 10-mL Becton, Dickinson and Company syringes. Three units of each container were stored at 4°C and 25°C. Concentration analysis was completed on study days 0, 2, 7, 14, 21, 28, 42, 56, 72, and 91 using a validated stability-indicating liquid chromatographic method with ultraviolet detection. Chemical stability was based on the intersection of the lower limit of the 95% confidence interval of the observed degradation rate and the time to achieve 90% of the initial concentration (T-90). The analytical method separated degradation products from epinephrine to measure concentration specifically, accurately, and reproducibly. During the study period, all solutions at 4°C retained more than 89.62% of the initial concentration for 91 days. Solutions stored at 25°C retained more than 90% for 21 days. Multiple linear regression revealed significant differences in percent remaining due to study day (P<0.001) and temperature (P=0.002). The calculated T-90, with 95% confidence, was 71.40 days for solutions stored at 4°C but only 12.77 days for solutions stored at 25°C. We conclude that 10 mcg/mL epinephrine solution diluted in 0.9% sodium chloride stored at 4°C is chemically and physically stable for 64 days, with 95% confidence. The syringe may be held at room temperature for up to 24 hours during this period and still retain more than 90% of the initial concentration.

Osteogenesis imperfecta (OI) type VI, a recessively inherited form of OI caused by mutations in SERPINF1 , is a severe form distinguished by osteomalacia on bone histomorphometry. We describe a boy with severe OI type VI who was initially treated with intravenous (IV) zoledronic acid (ZA) at 1.4 years of age; however, a year later he transitioned to denosumab 1 mg/kg sub-cutaneously every three months in an effort to decrease fracture rates. After two years on denosumab, he presented with symptomatic hypercalcemia due to the denosumab-induced, hyper-resorptive rebound phenomenon. Laboratory parameters at the time of the rebound were as follows: elevated serum ionized calcium (1.62 mmol/L, N 1.16–1.36), elevated serum creatinine due to hypercalcemia-induced muscle catabolism (83 µmol/L, N 9–55), and suppressed parathyroid hormone (PTH) (< 0.7 pmol/L, N 1.3–5.8). The hypercalcemia was responsive to low-dose IV pamidronate, with a rapid decline in serum ionized calcium, and otherwise normalization of the aforementioned parameters within 10 days. To benefit from the powerful, albeit short-term, anti-resorptive effect of denosumab without further rebound episodes, he was treated thereafter with denosumab 1 mg/kg alternating every three months with IV ZA 0.025 mg/kg. Five years later, he remained on dual alternating anti-resorptive therapy without further rebound episodes, and an overall improvement in his clinical status. This novel pharmacological approach of alternating short- and long-term anti-resorptive therapy every three months has not previously been described. Our report suggests this strategy may be an effective method for prevention of the rebound phenomenon in select children for whom denosumab may be beneficial.

PURPOSEPrevention of fractures is an unmet need in glucocorticoid (GC)-treated Duchenne muscular dystrophy. This study explored factors associated with incident vertebral fractures (VFs) to inform future fracture prevention efforts.METHODSVFs were evaluated prospectively at study baseline and 12 months on lateral spine radiographs in participants aged 4 to 25 years with Duchenne muscular dystrophy. Clinical factors were analyzed for their association with the change in Spinal Deformity Index (sum of the Genant-defined VF grades from T4 to L4) between baseline and 12 months.RESULTSThirty-eight males were evaluated (mean ± SD age at baseline 11.0 ± 3.6 years; mean ± SD GC duration at baseline 4.1 ± 3.1 years; 74% ambulatory). Nine of 38 participants (24%) had 17 incident VFs, of which 3/17 VFs (18%) were moderate/severe. Participants with 12-month incident VF had lower mean ± SD baseline lumbar spine areal bone mineral density Z-scores (-2.9 ± 1.0 vs -1.9 ± 1.1; P = .049) and lower total body less head areal bone mineral density Z-scores (-3.1 ± 1.2 vs -1.6 ± 1.7; P = .036). Multivariable linear regression showed that at least 1 VF at baseline (P < .001), a higher number of antecedent non-VF (P < .001), and greater bone age delay at baseline (P = .027) were significant predictors of an increase in the Spinal Deformity Index from baseline to 12 months.CONCLUSIONThe observation that ≥ 1 prevalent VF and/or non-VF were the strongest predictors of incident VFs at 12 months supports the need for prevention of first fractures in this high-risk setting. Bone age delay, a marker of GC exposure, may assist in the prioritization of patients in efforts to prevent first fractures.

An oral liquid formulation of nadolol, which is required for administration to patients who cannot swallow intact tablets, is not commercially available. The objective of this study was to evaluate the stability of nadolol 10 mg/mL prepared in Oral Mix vehicle and stored in amber glass, amber polyethylene terephthalate, or amber polyvinyl chloride for 91 days at 4ÆC and 25ÆC; and polypropylene oral plastic syringes at 25ÆC only. Three separate batches of nadolol suspension 10 mg/mL were prepared with Oral Mix. Of the suspension, 50-mL aliquots were stored in 100-mL bottles (amber glass, amber polyethylene terephthalate, or amber polyvinyl chloride). Half of the bottles from each container type were stored at 25ÆC and the other half at 4ÆC. On study days 0, 2, 7, 14, 21, 28, 42, 56, 72, and 91, nadolol concentration was determined using a reverse-phase, stability-indicating liquid chromatographic method from samples drawn from each type of container at each temperature. Oral syringes (3 mL), filled with 2 mL of suspension, were stored at 25ÆC and tested on days 0, 2, 7, 21, 42, and 91. The concentration of nadolol 10 mg/mL in Oral Mix in all study samples from bottles and oral syringes remained within 3.5% of the initial concentration. Based on the fastest degradation rate with 95% confidence, on day 91, between 99% to 100% and 98% to 100% remained in suspensions stored in bottles at 25ÆC and 4ÆC, respectively. Oral syringes at 25ÆC had 94% remaining on day 91. Multiple linear regression analysis demonstrated that the percent remaining was related to study day and container, but not temperature. On day 91, nadolol 10 mg/mL oral suspensions prepared with Oral Mix and stored in all bottle types at 4ÆC will retain more than 98% of the initial concentration compared to 99% at 25ÆC and only 94% when stored in oral syringes.

Background: Clozapine oral suspension is not commercially available in Canada but is required for administration to patients who cannot swallow intact tablets. Objective: To evaluate the stability of 25 mg/mL and 50 mg/mL clozapine suspensions prepared in a 50:50 mixture of methylcellulose gel 1% and Oral Syrup (flavoured syrup vehicle, Medisca Pharmaceutique Inc) and stored in amber glycol-modified polyethylene terephthalate (PET-G) bottles over 120 days at 4°C and 25°C. Methods: This study used a validated reverse-phase stability-indicating liquid chromatographic method capable of quantifying clozapine, 3 known degradation compounds, a known impurity, and an unknown compound. Three separate batches of 25 mg/mL and 50 mg/mL clozapine suspensions were prepared, divided into 100-mL aliquots, and stored in 120-mL PET-G bottles. Half of the bottles from each concentration were stored at room temperature (20°C to 25°C) and the other half were stored in the refrigerator (2°C to 8°C). On study days 0, 28, 60, 90, and 120, concentrations of clozapine, each of the 3 known clozapine degradation products, a known impurity, and an unknown compound were determined. Results: When suspensions were stored in PET-G containers at room temperature or under refrigeration for 120 days, the concentration of clozapine remained above 95% of initial concentration, and the measured concentration of degradation products and impurities did not exceed the 0.5% limits set by regulatory authorities worldwide. The proportion of the initial concentration of clozapine remaining on day 120, based on fastest degradation rate with 95% confidence (1-sided), exceeded 92%, and the only degradation product found (clozapine lactam, 0.2%) and an unknown impurity (0.2%) also did not exceed allowable limits. Conclusions: Compounded clozapine suspensions of 25 mg/mL and 50 mg/mL can be stored in amber PET-G containers for up to 120 days after preparation with storage at room temperature or under refrigeration. RÉSUMÉ Contexte : La clozapine en suspension orale n’est pas disponible sur le marché canadien, mais elle est nécessaire pour les patients qui ne peuvent l’avaler sous forme de comprimé intact. Objectif : Évaluer la stabilité des suspensions de clozapine de 25 mg/mL et de 50 mg/mL, préparées dans un mélange 50:50 de gel méthylcellulose à 1 % et de Sirop Oral (véhicule de sirop aromatisé, MEDISCA) et conservées dans des flacons ambrés en polytéréphtalate d’éthylène modifié au glycol (PET-G) pendant 120 jours à des températures de 4°C et 25°C. Méthode : Cette étude a utilisé une méthode validée par chromatographie liquide indicatrice de stabilité en phase inverse pouvant quantifier la clozapine, trois composés de dégradation connus, une impureté connue et un composé inconnu. Trois lots séparés de suspensions de clozapine de 25 mg/mL et de 50 mg/mL ont été préparés, divisés dans des aliquotes de 100-mL et stockés dans des flacons en PET-G de 120-mL. La moitié des flacons de chaque concentration a été conservée à température ambiante (de 20°C à 25°C), et l’autre moitié au réfrigérateur (de 2°C à 8°C). Aux jours 0, 28, 60, 90 et 120 de l’étude, on a déterminé les concentrations de clozapine, celles de chacun des trois produits de dégradation de la clozapine, celles d’une impureté connue et d’un complexe inconnu. Résultats : Lorsque les suspensions étaient stockées dans des contenants en PET-G à température ambiante et réfrigérées pendant 120 jours, la concentration de clozapine demeurait au-dessus de 95 % de la concentration initiale; la concentration mesurée des produits de dégradation et des impuretés ne dépassait pas la limite de 0,5 % fixée par les autorités de règlementation mondiales. La proportion de concentration initiale de clozapine restante au 120e jour, sur la base du taux de dégradation le plus rapide avec un intervalle de confiance de 95 % (unilatéral), dépassait 92 %, et le seul produit de dégradation trouvé (clozapine lactam, 0,2 %) ainsi qu’une impureté inconnue (0,2 %) ne dépassaient pas non plus les limites autorisées. Conclusions : Les suspensions de clozapine composées de 25 mg/mL et de 50 mg/mL peuvent être conservées dans des contenants ambrés PET-G jusqu’à 120 jours après leur préparation, soit à température ambiante, soit dans un réfrigérateur.

BACKGROUND:Trimethoprim (TMP) and sulfamethoxazole (SMX) are widely used, in combination, to treat or prevent various infections. Unfortunately, no liquid oral formulation is currently available in Canada for patients who are unable to swallow tablets.OBJECTIVE:To evaluate the stability of suspensions of TMP and SMX (8 and 40 mg/mL, respectively) prepared in Oral Mix or Oral Mix SF vehicle (Medisca Pharmaceutique Inc) and stored for up to 90 days in amber plastic bottles or amber plastic syringes at 5°C or 25°C.METHODS:Suspensions were prepared from bulk powder and from tablets in Oral Mix and Oral Mix SF vehicles, then transferred to amber plastic (polyethylene terephthalate glycol) bottles and plastic oral syringes and stored at 5°C and 25°C. Samples were collected on predetermined study days (0, 7, 14, 23, 45, 60, 75, and 90 days) and analyzed using a validated high-performance liquid chromatography - ultraviolet detection method. A suspension was considered stable if it maintained at least 90% of its initial concentration with 95% confidence. Observations of organoleptic characteristics such as colour and odour, as well as pH, were used to assess physical stability.RESULTS:Suspensions prepared from bulk powder maintained concentrations of TMP and SMX of at least 97% of the initial concentration over the 90-day study period. No obvious changes in colour, odour, or pH were observed. However, acceptable suspensions could not be prepared from the commercial tablets. A persistent foam that developed at the surface of all suspensions prepared from tablets could result in inconsistent dosing.CONCLUSIONS:Extemporaneously compounded oral suspensions of TMP and SMX (8 and 40 mg/mL, respectively) prepared from bulk powder in Oral Mix and Oral Mix SF vehicles and stored in amber plastic bottles or syringes at 5°C or 25°C remained stable for at least 90 days. Suspensions made from tablets produced unacceptable formulations.

Background Sepsis is a health problem of global importance; treatments focus on controlling infection and supporting failing organs. Recent clinical research suggests that intravenous vitamin C may decrease mortality in sepsis. We have designed a randomized controlled trial (RCT) to ascertain the effect of vitamin C on the composite endpoint of death or persistent organ dysfunction at 28 days in patients with sepsis. Methods LOVIT (Lessening Organ dysfunction with VITamin C) is a multicenter, parallel-group, blinded (participants, clinicians, study personnel, Steering Committee members, data analysts), superiority RCT (minimum n = 800). Eligible patients have sepsis as the diagnosis for admission to the intensive care unit (ICU) and are receiving vasopressors. Those admitted to the ICU for more than 24 h are excluded. Eligible patients are randomized to high-dose intravenous vitamin C (50 mg/kg every 6 h for 96 h) or placebo. The primary outcome is a composite of death or persistent organ dysfunction (need for vasopressors, invasive mechanical ventilation, or new and persisting renal replacement therapy) at day 28. Secondary outcomes include persistent organ dysfunction-free days to day 28, mortality and health-related quality of life at 6 months, biomarkers of dysoxia, inflammation, infection, endothelial function, and adverse effects (hemolysis, acute kidney injury, and hypoglycemia). Six subgroup analyses are planned. Discussion This RCT will provide evidence of the effect of high-dose intravenous vitamin C on patient-important outcomes in patients with sepsis. Trial registration clinicaltrials.gov, NCT03680274 , first posted 21 September 2018.

Finasteride is not commercially available in a liquid format, which stimulated the development of a stable and simple finasteride suspension formulation. The objectives of this work were to develop and test a finasteride suspension for 1) simplicity to compound, 2) pharmaceutical acceptability, 3) stability, and 4) potential for occupational exposure. The stability of commercial 5-mg finasteride tablets (50 mg/150 mL) was evaluated in water, Oral Mix, and OralMix SF in amber polyethylene terephthalate bottles at 25°C or 4°C. Additional stability studies were carried out using sugar-free Finasteride Powder USP in amber polyethylene terephthalate bottles and tablets in water in polypropylene oral syringes. On study days 0, 1, 3, 7, 14, 28, 38, 49, 63, and 90, the finasteride concentration was determined using a validated stability-indicating liquid chromatographic method. The potential occupational airborne exposure was evaluated by attempting to measure finasteride in 1000 liters of room air following shaking and nebulization. Finasteride suspension/dispersion formulations were prepared in water, Oral Mix, and Oral Mix SF from tablets and pure powder. All formulations retained more than 94.3% of the initial finasteride concentration, with 95% confidence, when stored for up to 90 days at room temperature or 4°C. Simulations of occupational exposure failed to demonstrate the presence of finasteride in room air following attempts to nebulize finasteride mixtures. We conclude that 333-µg/mL suspension/dispersions of finasteride in water or Oral Mix products will have more than 94.3% of the initial finasteride concentration remaining after 90 days, regardless of the formulation, container, or storage temperature. Although we could not detect finasteride in room air, given the analytical limits of the study, we estimate that exposure would unlikely exceed 3.6-µg/1000 liters of room air. Nevertheless, since current regulations are based on "no safe limit," use of primary engineering controls and personal protective equipment as appropriate is recommended.

BACKGROUNDAntimicrobial Resistance (AMR) constitutes an international public health threat widely believed to result from excessive antimicrobial use (AMU). Numerous authorities have recommended Antimicrobial Stewardship Programs (ASP) to curb the selection of AMR but, there is a lack of data confirming this benefit.METHODSA controlled interrupted time series study spanning 14-years was performed to assess impact of a comprehensive hospital-based ASP that included pharmacist-led audit-and-feedback on institutional AMR. Patient-level microbiologic and AMU data were obtained from October 2002 to September 2016. Poisson regression models were used to identify changes in the incidence and trend of hospital-acquired (HA-) Antibiotic Resistant Organisms (ARO) and Multidrug-Resistant Organisms (MDRO). Changes in community-acquired (CA-) ARO, CA-MDRO, and inpatient AMU were assessed as controls and process outcomes.RESULTSStatistically significant shifts in AMU, HA-ARO, and HA-MDRO trends coinciding with ASP implementation were observed, corresponding with a 9% reduction in HA-ARO burden (IRR 0.91, 95%CI 0.83-0.99; p=0.03) and 13% reduction in HA-MDRO burden (IRR 0.87, 95% CI 0.73-1.04; p=0.13) in the intervention period. In contrast, CA-ARO and CA-MDRO incidence continued to rise with 40% (CA-ARO IRR 1.40, 95%CI 1.28-1.54; p<0.0001) and 68% (CA-MDRO IRR 1.68, 95%CI 1.57-1·82; p<0.0001) increases in burden found.CONCLUSIONSImplementation of a comprehensive ASP resulting in reduced AMU was associated with a significant reduction in institutional AMR, even though community AMR increased during the same period. These results confirm that ASPs play an important role in the fight against AMR.