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, rufinamide 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 A 1-mL sample was withdrawn from each of the 6 bottles with a micropipette immediately after preparation and at 7, 14, 28, 56, and 90 days.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 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.

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.

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.