David J. Hutchinson

Treatment of hypervolemic or euvolemic hyponatremia associated with heart failure, cirrhosis, or the syndrome of inappropriate antidiuretic hormone with tolvaptan: A clinical review

BACKGROUND Tolvaptan is an oral nonpeptide selective vasopressin V(2)-receptor antagonist indicated for the treatment of clinically relevant hypervolemic or euvolemic hyponatremia associated with heart failure, cirrhosis, or syndrome of inappropriate antidiuretic hormone. OBJECTIVE The objective of this article was to review the pharmacology, efficacy, and tolerability of tolvaptan in the treatment of hypervolemic or euvolemic hyponatremia, heart failure, and autosomal dominant polycystic kidney disease (ADPKD). METHODS Articles were identified using MEDLINE (1966-February 28, 2010) and EMBASE (1947-February 28, 2010). Abstracts and proceedings from the annual meetings (2007-2009) of the American Heart Association, the European Society of Cardiology, and the American Society of Nephrology were searched to identify additional relevant publications. Searches were conducted using the terms tolvaptan, vasopressin antagonist, heart failure, polycystic kidney disease, hyponatremia, drug interaction, pharmacokinetics, and pharmacology. The reference lists of the identified publications were reviewed for additional references. All clinical trials that assessed the use of tolvaptan in the management of hypervolemic/euvolemic hyponatremia or heart failure in humans were included, regardless of study design. RESULTS A total of 9 trials were identified. For the treatment of hyponatremia, tolvaptan was associated with significantly increased serum sodium concentrations compared with placebo on treatment days 4 (3.62 [2.68] vs 0.25 [2.08] mmol/L, respectively; P < 0.001) and 30 (6.22 [4.10] vs 1.66 [3.59] mmol/L; P < 0.001). In the clinical trials in patients with heart failure, tolvaptan at doses of 30, 60, and 90 mg/d was associated with mean weight changes of -1.80, -2.10, and -2.05 kg, respectively, versus -0.60 kg with placebo (P = 0.002, P = 0.002, and P = 0.009). Trials of tolvaptan in humans with ADPKD are ongoing. Overall, mortality rates were not significantly altered with tolvaptan compared with placebo (25.9% vs 26.3%). The most commonly reported adverse events associated with tolvaptan in clinical trials were dry mouth (4.2%-23.0%), thirst (7.7%-40.3%), and polyuria (0.6%-31.7%), all consistent with the mechanism of action of the drug. CONCLUSION Based on findings from clinical trials to date, tolvaptan is effective for the correction of hyponatremia but has not been associated with significant improvements in mortality in patients with heart failure compared with placebo, and its utility in the treatment of ADPKD in humans remains to be determined.

Inhaled aztreonam lysine: an evidence-based review

Introduction: Chronic airway infection in cystic fibrosis (CF) is linked with progressive loss of pulmonary function and is the primary cause of mortality. Treatment regimens have generally focused on the use of chronic antibiotic therapy to target Pseudomonas aeruginosa (PA), a major pathogen associated with a decline in FEV1%. Specifically, inhaled antibiotic therapy provides high antibiotic sputum concentrations and decreases bacterial burden. Areas covered: This article describes the pharmacology, pharmacodynamics/pharmacokinetics, clinical efficacy, microbiology and safety of aztreonam lysine (AZLI, Cayston), an inhaled antibiotic indicated for use in CF patients with PA. Articles were identified using MEDLINE (1966 – June 13, 2013) and EMBASE (1947 – June 13, 2013). Abstracts from the annual meeting (2011 – 2012) of the North American Cystic Fibrosis Conference were searched to identify additional publications. Expert opinion: AZLI is an additional product that can be used in the management of CF and will likely play a major role in the suppression of PA. Clinical trials have demonstrated improvements in pulmonary function and patient reported symptoms. AZLI may therefore be used as an alternative to traditional inhaled antibiotics in patients with moderate-to-severe CF and PA colonization. Further investigation is warranted into use of AZLI in mild lung disease and for PA eradication.

Respiratory Syncytial Virus Prophylaxis in Special Populations: Is it Something Worth Considering in Cystic Fibrosis and Immunosuppression?

Respiratory syncytial virus (RSV) bronchiolitis is the leading cause of infant hospitalization in the United States. Prophylaxis with palivizumab is effective in reducing RSV hospitalizations in premature infants and in infants or children with chronic lung disease or congenital heart disease. Patients with CF or those who are immunocompromised may be at increased risk for RSV infection-related complications; hence, prophylaxis may prove beneficial to these populations. The extent of palivizumab use in the CF and immunocompromised populations is variable. Palivizumab appears to be safe and may be effective in infants and young children with CF and immunocompromise. However, well-designed, randomized, controlled trials published in peer-reviewed journals are lacking, and its routine use can therefore not be recommended at this time. If used in patients with CF or those who are immunocompromised, RSV prophylaxis should be restricted to peak outbreak months in order to optimize the cost benefit of palivizumab.

Education in Pediatrics in US Colleges and Schools of Pharmacy

Objective. To determine the extent to which pediatrics is taught at US doctor of pharmacy (PharmD) programs and to characterize what is being taught and how. Methods. A 40-question online survey instrument was sent to accredited and candidate-status US PharmD programs. Results. Of 86 participating programs (67.2% response rate), 81 (94.2%) indicated that pediatric topics were included in their required classroom curricula (mean, 21.9 contact hours). A pediatric elective course was offered by 61.0% of programs (mean, 25.9 contact hours). Advanced pharmacy practice experiences (APPEs) in pediatrics were offered by 97.4% of programs, with an average of 27 students per program completing this practice experience annually. Conclusions. Almost all responding programs incorporated pediatrics in their required curricula. Pediatric elective courses provided an adequate mean number of contact hours, but 39.0% of programs did not offer an elective course. One-fifth of students completed a pediatric APPE prior to graduation. Continued expansion of pediatric-focused classroom and experiential curricula across US PharmD programs is recommended.

Stability of extemporaneously prepared moxifloxacin oral suspensions

PURPOSE The stability of extemporaneously prepared moxifloxacin oral suspensions was studied. METHODS An oral suspension of moxifloxacin 20 mg/mL was prepared by thoroughly grinding three 400-mg tablets of moxifloxacin in a glass mortar. Thirty milliliters of Ora-Plus and 30 mL of either Ora-Sweet or Ora-Sweet SF were mixed and added to the powder to make a final volume of 60 mL. Three identical samples of each formulation were prepared and placed in 2-oz amber plastic bottles with child-resistant caps and were stored at room temperature (23-25 degrees C). A 1-mL sample was withdrawn from each of the six bottles with a micropipette immediately after preparation and at 7, 14, 28, 60, and 90 days. After further dilution to an expected concentration of 8 microg/ mL with sample diluent, the samples were assayed in duplicate by stability-indicating high-performance liquid chromatography. Stability was defined as the retention of at least 90% of the initial concentration. RESULTS At least 99% of the initial moxifloxacin remained throughout the 90-day study period in both preparations. There were no detectable changes in color, odor, taste, and pH and no visible microbial growth in any sample. CONCLUSION Extemporaneously compounded suspensions of moxifloxacin 20 mg/mL in a 1:1 mixture of Ora-Plus and Ora-Sweet or Ora-Sweet SF were stable for at least 90 days when stored in 2-oz amber plastic bottles at room temperature.

Stability of Extemporaneously Prepared Rufinamide Oral Suspensions

Background: Rufinamide is an oral antiepileptic drug indicated for adjunctive therapy in treating generalized seizures associated with Lennox-Gastaut syndrome. Currently, rufinanide is available as 200-mg and 400-mg tablets. A liquid dosage form does not exist at the present time. Lack of a suspension formulation may present an administration problem for many children and adults who are unable to swallow tablets. The availability of a liquid dosage form will provide an easy and accurate way to measure and administer the medication. Objective: To determine the stability of both sugar-containing and sugar-free rufinamide suspensions over a 90-day period. Methods: A suspension of rufinamide 40 mg/mL was prepared by grinding twelve 400-mg tablets of rufinamide tablets in a glass mortar. Sixty milliliters of Ora-Plus and 60 mL of either Ora-Sweet or Ora-Sweet SF (sugar free) were mixed and added to the powder to make a final volume of 120 mL. Three identical samples of each formulation were prepared and placed in 60-mL amber plastic bottles and were stored at room temperature. A 1-mL sample was withdrawn from each of the 6 bottles with a micropipette immediately after preparation and at 7, 14, 28, 56, and 90 days. After further dilution to an expected concentration of 0.4 mg/mL, the samples were assayed using high-performance liquid chromatography. Stability was defined as the retention of at least 90% of the initial concentration. Results: At least 90% of the initial rufinamide concentration remained throughout the 90-day study period in both preparations. There were no detectable changes in color, odor, taste, and pH and no visible microbial growth. Conclusions: Extemporaneously compounded suspensions of rufinamide 40 mg/mL in a 1:1 mixture of Ora-Plus and Ora-Sweet or Ora-Sweet SF were stable for at least 90 days when stored in 59-mL amber polypropylene plastic bottles at room temperature.

Stability of diluted adenosine solutions in polyvinyl chloride infusion bags

PURPOSE The stability of diluted adenosine solutions in polyvinyl chloride infusion bags was studied. METHODS Adenosine 50-, 100-, and 220-μg/mL solutions were prepared in 50-mL polyvinyl chloride (PVC) infusion bags containing 0.9% sodium chloride injection or 5% dextrose injection and stored at room temperature (23-25 °C) or under refrigeration (2-8 °C). Each sample of every combination of concentration, diluent, and storage temperature was prepared in triplicate, yielding 36 samples. The samples were assayed using a stability-indicating, reverse-phase high-performance liquid chromatographic method immediately after preparation (time zero) and at 24 hours, 48 hours, 7 days, and 14 days. pH was measured at time zero, 48 hours, 7 days, and 14 days. Time zero concentrations were calculated from the equation produced from a calibration curve of standards ranging from 10 to 500 μg/mL. Samples were also visually inspected against a light background for clarity, color, and the presence of crystalline particulate matter. Stability was defined as retaining at least 90% of the initial adenosine concentration. RESULTS After 14 days, all samples retained greater than 98% of the initial adenosine concentration, with no evidence of adsorption, visible precipitation, or considerable change in pH, suggesting minimal to no loss of product due to degradation or adsorption. CONCLUSION Adenosine 50-, 100-, and 220-μg/mL solutions in 50-mL PVC infusion bags containing 0.9% sodium chloride injection or 5% dextrose injection stored at room temperature and refrigerated conditions were stable for at least 14 days.

Stability of Diluted Adenosine Solutions in Polyolefin Infusion Bags

Background Intravenous or intracoronary adenosine is used in the cardiac catherization lab to achieve maximal coronary blood flow and determine fractional flow reserve. Objective To determine the stability of adenosine 10 and 50 µg/mL in either 0.9% sodium chloride injection or 5% dextrose injection in polyolefin infusion bags stored at 2 temperatures, refrigeration (2°C-8°C) or controlled room temperature (20°C-25°C). Methods Adenosine 10 µg/mL and 50 µg/mL solutions were prepared in 50 mL polyolefin infusion bags containing 0.9% sodium chloride injection or 5% dextrose injection and stored at controlled room temperature or under refrigeration. Each combination of concentration, diluent, and storage was prepared in triplicate. Samples were assayed using stability-indicating, reversed-phase high-performance liquid chromatography immediately at time 0 and at 24 hours, 48 hours, 7 days, and 14 days. Stability was defined as retaining 90% to 110% of the initial adenosine concentration. The samples were also visually inspected against a light background for clarity, color, and the presence of particulate matter. Results After 14 days, all samples retained 99% to 101% of the initial adenosine concentration. No considerable change in pH or visual appearance was noted. The stability data indicated no significant loss of drug due to chemical degradation or physical interactions during storage. Conclusion Adenosine solutions of 10 and 50 µg/mL were stable for at least 14 days in 50 mL polyolefin infusion bags of 0.9% sodium chloride injection or 5% dextrose injection stored at controlled room temperature and refrigerated conditions.

Stability of extemporaneously prepared cinacalcet oral suspensions

PURPOSE The stability of extemporaneously prepared cinacalcet suspensions over 90 days was evaluated. METHODS Cinacalcet 5-mg/mL suspension was prepared by triturating 30-mg cinacalcet tablets. Twelve 30-mL batches were prepared with a 1:1 mixture of Ora-Plus and either Ora-Sweet or Ora-Sweet SF (sugar free). Three suspensions of each kind were stored at both room temperature and refrigerated conditions. A 1-mL sample was taken from each bottle at 0, 7, 18, 32, 64, and 90 days. Each sample was assayed using high-performance liquid chromatography (HPLC). A new HPLC method for evaluating drug peaks of pure cinacalcet was developed. Stability was defined as retention of at least 90% of the initial drug concentration. RESULTS The HPLC method established in this study serves as a novel assay for evaluating cinacalcet oral suspensions. For all suspensions tested at individual conditions, the concentration remained above 90% of the initial concentration for 90 days of storage with the exception of Ora-Plus and Ora-Sweet SF suspensions stored under refrigeration, which were stable for 64 days. Usual sedimentation of the suspensions occurred over time but resolved with agitation; there was no other change in visual appearance of the suspensions over the course of the 90-day study. The color and odor of the suspensions throughout the study remained unchanged with respect to the initial time point. CONCLUSION Extemporaneously compounded cinacalcet 5-mg/mL oral suspensions prepared with a 1:1 mixture of Ora-Plus and either Ora-Sweet or Ora-Sweet SF and stored in 2-oz amber polypropylene plastic bottles were stable for at least 64 days at room temperature and under refrigeration.