Canadian clinical practice guidelines for acute and chronic rhinosinusitis.

This document provides healthcare practitioners with information regarding the management of acute rhinosinusitis (ARS) and chronic rhinosinusitis (CRS) to enable them to better meet the needs of this patient population. These guidelines describe controversies in the management of acute bacterial rhinosinusitis (ABRS) and include recommendations that take into account changes in the bacteriologic landscape. Recent guidelines in ABRS have been released by American and European groups as recently as 2007, but these are either limited in their coverage of the subject of CRS, do not follow an evidence-based strategy, or omit relevant stakeholders in guidelines development, and do not address the particulars of the Canadian healthcare environment.Advances in understanding the pathophysiology of CRS, along with the development of appropriate therapeutic strategies, have improved outcomes for patients with CRS. CRS now affects large numbers of patients globally and primary care practitioners are confronted by this disease on a daily basis. Although initially considered a chronic bacterial infection, CRS is now recognized as having multiple distinct components (eg, infection, inflammation), which have led to changes in therapeutic approaches (eg, increased use of corticosteroids). The role of bacteria in the persistence of chronic infections, and the roles of surgical and medical management are evolving. Although evidence is limited, guidance for managing patients with CRS would help practitioners less experienced in this area offer rational care. It is no longer reasonable to manage CRS as a prolonged version of ARS, but rather, specific therapeutic strategies adapted to pathogenesis must be developed and diffused.Guidelines must take into account all available evidence and incorporate these in an unbiased fashion into management recommendations based on the quality of evidence, therapeutic benefit, and risks incurred. This document is focused on readability rather than completeness, yet covers relevant information, offers summaries of areas where considerable evidence exists, and provides recommendations with an assessment of strength of the evidence base and degree of endorsement by the multidisciplinary expert group preparing the document.These guidelines have been copublished in both Allergy, Asthma & Clinical Immunology and the Journal of Otolaryngology-Head and Neck Surgery.

Comparison of the stability of split and intact gabapentin tablets.

The purpose of this study was to determine the stability differences between split and intact gabapentin tablets. Gabapentin tablets from three different manufacturers (G1, G2 and G3) were tested for a period of 9 weeks under long-term (25 degrees C/60% RH) and intermediate stability (30 degrees C/60% RH) storage conditions after storage in closed amber pharmacy dispensing containers. Samples were analyzed for dissolution and potency using validated HPLC methods. Potency test also included the quantitation of gabapentin's main degradation product. Tablets from all manufacturers and at all time points had potency >90%. At 9 weeks, a statistically significant decrease (p<0.02) in gabapentin potency was observed for the whole and split G2 and G3 tablets under the intermediate storage conditions. At the end of 9 weeks, all samples also showed slightly higher levels of degradation product which was statistically significant (p<0.01) for samples stored under intermediate stability storage conditions and exceeded the proposed USP (PF, 2006) limit for the G3 split and intact tablets. No difference was observed between the potency and dissolution of the intact and the split tablets from the same manufacturer and the three products tested remained stable throughout the study period. The results suggest that splitting of gabapentin tablets did not affect the stability of these particular drug products tested as part of this study when stored under normal storage conditions for a period of up to 9 weeks. However, the results should not be extrapolated to other gabapentin drug products and to other tablet dosage forms.

Development and application of a validated HPLC method for the analysis of dissolution samples of gabapentin drug products.

A simple isocratic reversed-phase HPLC method was developed and validated for the analysis of dissolution samples of gabapentin tablets and capsules. Separation of gabapentin from its major degradation impurity, 3,3-pentamethylene-4-butyrolactam was achieved on a Phenomenex Luna Cyano column using a methanol-acetonitrile-20 mM KH(2)PO(4) (pH 2.2) (5:5:90, v/v/v) mobile phase. The compounds were eluted isocratically at a flow rate of 1.25 mL/min. Both compounds were analyzed with UV detection at 210 nm. The method was validated according to USP Category I requirements for gabapentin. The validation characteristics included accuracy, precision, linearity, range, specificity and limit of quantitation. Robustness testing was also conducted to evaluate the effect of minor changes to the chromatographic system and to establish appropriate system suitability parameters. Validation acceptance criteria were met in all cases. This method was used successfully for the quality assessment of five gabapentin drug products.

A headspace-gas chromatography method for isopropanol determination in warfarin sodium products as a measure of drug crystallinity.

Coumadin® a nd s everal generic products of warfarin s odium (WS) contain the crystalline form (clathrate) in which WS and isopropanol (IPA) are associated in a 2:1 molar ratio. IPA is critical in maintaining the WS crystalline structure. Physicochemical properties of the drug and drug product may change when the crystalline drug transforms to amorphous form. A headspace-gas chromatography (HS-GC) method was developed and validated for IPA determination in the WS drug product. n-propanol (NPA) was used as internal standard and the method was validated for specificity, system suitability, linearity, accuracy, precision, range, limits of detection and quantification, and robustness. The method was specific, with good resolution between IPA and NPA peaks. Chromatographic parameters (retention time, IPA/NPA area ratio, tailing factor, theoretical plates, USP symmetry, capacity factor, selectivity and resolution) were consistent over three days of validation. The analytical method was linear from 2-200 µg mL-1 (0.1- 10 % IPA present in the drug product). LOD and LOQ were 0.1 and 2 µg mL-1, respectively. Accuracy at low (2 µg mL-1) and high (200 µg mL-1) IPA concentrations of the calibration curve was 103.3-113.3 and 98.9-102.2 % of the nominal value, resp. The validated method was precise, as indicated by the RSD value of less than 2 % at three concentration levels of the calibration curve. The method reported here was utilized to determine accurately and precisely the IPA content in in-house formulations and commercial products. In summary, IPA determination by HS-GC provides an indirect measure of WS crystallinity in the drug product. Nevertheless, it should be confirmed by another analytical method since IPA from the drug substance is not distinguishable from IPA that may be present outside the drug crystals in a dosage form when prepared by wet granulation with IPA.

Development and application of a validated HPLC method for the determination of gabapentin and its major degradation impurity in drug products.

A simple isocratic reversed-phase HPLC method for the determination of gabapentin and its major degradation impurity, 3,3-pentamethylene-4-butyrolactam, was developed and validated for use in the analysis of pharmaceutical tablets and capsules. Separation was achieved on a Brownlee Spheri-5 Cyano column using an acetonitrile-10 mM KH2PO4/10 mM K2HPO4 (pH 6.2) (8:92, v/v) mobile phase. The compounds were eluted isocratically at a flow rate of 1 mL/min. Both compounds were analyzed with UV detection at 210 nm. The method was validated according to USP Category I requirements for gabapentin and USP Category II for 3,3-pentamethylene-4-butyrolactam. The validation characteristics included accuracy, precision, linearity, range, specificity, limit of quantitation and robustness. Validation acceptance criteria were met in all cases. This method was used successfully for the quality assessment of four gabapentin drug products.

Dose Uniformity of Scored and Unscored Tablets: Application of the FDA Tablet Scoring Guidance for Industry.

PURPOSE: This U.S. Food and Drug Administration (FDA) laboratory study examines the impact of tablet splitting, the effect of tablet splitters, and the presence of a tablet score on the dose uniformity of two model drugs. METHODS: Whole tablets were purchased from five manufacturers for amlodipine and six for gabapentin. Two splitters were used for each drug product, and the gabapentin tablets were also split by hand. Whole and split amlodipine tablets were tested for content uniformity following the general chapter of the United States Pharmacopeia (USP) Uniformity of Dosage Units <905>, which is a requirement of the new FDA Guidance for Industry on tablet scoring. The USP weight variation method was used for gabapentin split tablets based on the recommendation of the guidance. RESULTS: All whole tablets met the USP acceptance criteria for the Uniformity of Dosage Units. Variation in whole tablet content ranged from 0.5 to 2.1 standard deviation (SD) of the percent label claim. Splitting the unscored amlodipine tablets resulted in a significant increase in dose variability of 6.5-25.4 SD when compared to whole tablets. Split tablets from all amlodipine drug products did not meet the USP acceptance criteria for content uniformity. Variation in the weight for gabapentin split tablets was greater than the whole tablets, ranging from 1.3 to 9.3 SD. All fully scored gabapentin products met the USP acceptance criteria for weight variation. CONCLUSION: Size, shape, and the presence or absence of a tablet score can affect the content uniformity and weight variation of amlodipine and gabapentin tablets. Tablet splitting produced higher variability. Differences in dose variability and fragmentation were observed between tablet splitters and hand splitting. These results are consistent with the FDA's concerns that tablet splitting can have an effect on the amount of drug present in a split tablet and available for absorption. LAY ABSTRACT: Tablet splitting has become a very common practice in the United States and throughout the world. Tablets are often split to modify dose strength, make swallowing easier, and reduce cost to the consumer. To better address product quality for this widely used practice, the U.S. Food and Drug Administration (FDA) published a Guidance for Industry that addresses tablet splitting. The guidance provides testing criteria for scored tablets, which is a part of the FDA review process for drugs. The model drugs selected for this study were amlodipine and gabapentin, which have different sizes, shapes, and tablet scores. Whole and split amlodipine tablets were tested for drug content because of a concern that the low-dose strength may cause greater variability. Whole and split gabapentin tablets were tested for weight variation because of their higher dosage strength of 600 mg. All whole tablets met the acceptance criteria for the Uniformity of Dosage Units based on the guidance recommendations. When unscored amlodipine tablets were split by a splitter, all formulations did not meet the acceptance criteria. When fully scored gabapentin tablets were split by hand and by splitter, they met the acceptance criteria. The findings of this FDA study indicated physical characteristics such as size, shape, and tablet score can affect the uniformity of split tablets.

Determination of plasma and brain levels of isotretinoin in mice following single oral dose by high-performance liquid chromatography.

An isocratic reversed-phase high-performance liquid chromatographic method was established and validated according to FDA's Guidance for Industry, "Bioanalytical Method Validation", for the determination of isotretinoin in plasma and brain tissue from mice following single and multiple oral doses of Accutane. Plasma sample preparation included deproteination with acetonitrile-perchloric acid followed by centrifugation. Brain tissue was homogenized and extracted with acetonitrile-perchloric acid followed by centrifugation. The supernatants were analyzed by high-performance liquid chromatography (HPLC). Benz[alpha]anthrancene-7,12-dione was used as the internal standard. Chromatographic separation was achieved on a C18 column using an acetonitrile-aqueous 0.5% acetic acid (85:15, v/v) elution. The average extraction efficiency was >95% for plasma and >82% for brain. The lower limit of quantification was 30 ng/mL for plasma and was 30 ng/0.1g for brain tissue, respectively. The linear range for plasma was 30-600 ng/mL, and 15-300 ng/0.1g for brain. Maximum concentrations of isotretinoin in both plasma and brain were observed at 1h after single oral dosing (25 mg/kg). The maximum concentrations in plasma and brain were 2.36 microg/mL and 0.34 microg/g, respectively. The mean area under curve (AUC) in plasma was 6.13 microg h/mL. The mean eliminate half-life in plasma was estimated as 46 min.

Evaluation of In-Use Stability of Anticoagulant Drug Products: Warfarin Sodium.

The objective of the study was to evaluate the stability of warfarin products during use by patients or caregivers. For evaluation, three commercial products manufactured by different processes were selected and placed at 30°C/75%RH to simulate in use condition. Samples were withdrawn up to 12 weeks and analyzed for the physicochemical changes. Scanning electron microscopy demonstrated increasing holes and craters in the tablets over the timeframe. Near-infrared chemical imaging and powder X-ray powder diffraction corroborated the change arising from conversion of crystalline to amorphous forms of the drug. Hardness and disintegration time of the tablets were found to increase progressively. With increasing time, moisture contents of the products were found to increase and consequent decrease in isopropyl alcohol content of the product. Dissolution of the tablets in media at pH 4.5 demonstrated discrimination between crystalline and amorphous drug products. Overall, percent drug dissolved in each product at 30 min was found to decrease with increasing exposure time. Dissolution of drug decreased from 54% to 38% and 82% to 54% for the two products while the third product maintained consistently high level of dissolution. These results suggest that the drug product quality attributes can change during use.

Canadian clinical practice guidelines for acute and chronic rhinosinusitis.

This document provides health care practitioners with information regarding the management of acute rhinosinusitis (ARS) and chronic rhinosinusitis (CRS) to enable them to better meet the needs of this patient population. These guidelines describe controversies in the management of acute bacterial rhinosinusitis (ABRS) and include recommendations that take into account changes in the bacteriologic landscape. Recent guidelines in ABRS have been released by American and European groups as recently as 2007, but these are either limited in their coverage of the subject of CRS, do not follow an evidence-based strategy, or omit relevant stakeholders in the development of guidelines and do not address the particulars of the Canadian health care environment.Advances in understanding the pathophysiology of CRS, along with the development of appropriate therapeutic strategies, have improved outcomes for patients with CRS. CRS now affects large numbers of patients globally, and primary care practitioners are confronted by this disease on a daily basis. Although initially considered a chronic bacterial infection, CRS is now recognized as having multiple distinct components (eg, infection, inflammation), which have led to changes in therapeutic approaches (eg, increased use of corticosteroids). The role of bacteria in the persistence of chronic infections and the roles of surgical and medical management are evolving. Although evidence is limited, guidance for managing patients with CRS would help practitioners less experienced in this area offer rational care. It is no longer reasonable to manage CRS as a prolonged version of ARS, but, rather, specific therapeutic strategies adapted to pathogenesis must be developed and diffused.Guidelines must take into account all available evidence and incorporate these in an unbiased fashion into management recommendations based on the quality of evidence, therapeutic benefit, and risks incurred. This document is focused on readability rather than completeness yet covers relevant information, offers summaries of areas where considerable evidence exists, and provides recommendations with an assessment of the strength of the evidence base and the degree of endorsement by the multidisciplinary expert group preparing the document.These guidelines have been copublished in both Allergy, Asthma, and Clinical Immunology and the Journal of Otolaryngology-Head and Neck Surgery.

Stability of gabapentin 300-mg capsules repackaged in unit dose containers.

PURPOSE: The stability of a gabapentin 300-mg capsule product in the original bulk containers and repackaged in unit dose blister strips was studied. METHODS: Both products were stored for one year under long-term storage conditions (25 degrees C and 60% relative humidity [RH]) and for three months under accelerated storage conditions (40 degrees C and 75% RH) and tested for weight change, potency, and dissolution using validated analytical method. RESULTS: The capsules in the original containers showed no change in weight during the study period. However, the repackaged drug product stored under long-term storage conditions and under accelerated storage conditions showed significant weight increases (p < 0.001) during the study period. No significant differences in potency between the original and repackaged drug products were detected. Potency exceeded 97% for the products stored under the long-term storage conditions and exceeded 95% for the products stored under the accelerated storage conditions. At 13 weeks, samples from the original container and the blister strips stored under the accelerated storage conditions showed quantitative levels of the lactam degradation product; however, these levels were within acceptable limits. No other difference was observed between the original and the repackaged drug products, and both products remained stable throughout the study period. CONCLUSION: Gabapentin 300-mg capsules in the original containers and repackaged in blister strips were stable up to one year under long-term storage conditions and up to three months under accelerated storage conditions.

The effect of food on the relative bioavailability of rapidly dissolving immediate-release solid oral products containing highly soluble drugs.

The purpose of this study is to test the hypothesis that rapidly dissolving immediate-release (IR) solid oral products containing a highly soluble and highly permeable drug [biopharmaceutical classification system (BCS) class I] are bioequivalent under fed conditions. Metoprolol and propranolol (BCS class I) as well as hydrochlorothiazide (BCS class III) were selected as model drugs. The relative bioavailability of two FDA approved (Orange Book AB rating) solid oral dosage forms of metoprolol and propranolol/hydrochlorothiazide (combination tablets) was evaluated in human volunteers under fed conditions using a two-way crossover design. Equal numbers of male and female volunteers were recruited, and racial and/or ethnic minorities were not excluded. The plasma concentrations of metoprolol, propranolol, and hydrochlorothiazide were determined using validated high-performance liquid chromatography (HPLC) methods. Eighteen subjects completed the metoprolol study while 17 subjects completed the propranolol/hydrochlorothiazide combination tablet study. In the metoprolol study, the 90% confidence intervals of Cmax and AUC(inf) were 98-118% and 92-115%, respectively. For propranolol, the 90% confidence intervals of Cmax and AUC(inf) were 91-121% and 89-117%, and for hydrochlorothiazide, the 90% confidence intervals for Cmax and AUC(inf) were 96-107% and 97-106%, respectively. These study results appear to support the hypothesis that rapidly dissolving IR solid oral products containing a BCS class I drug are likely to be bioequivalent under fed conditions. In addition, BCS class III drugs may have the potential to be bioequivalent under fed conditions.