RESUMEN
Allergic rhinitis (AR) and chronic idiopathic urticaria (CIU) are common causes of substantial illness and disability in preschool children. Antihistamines are commonly used to treat preschool children with these conditions, but their use is based mostly on extrapolated efficacy from adult populations; it is thus important to characterize the safety of antihistamines in the pediatric population. This study was designed to assess the safety of levocetirizine dihydrochloride oral liquid drops in infants and children with AR or CIU. Two multicenter, double-blind, randomized, parallel-group studies randomized infants aged 6-11 months (study 1, n = 69) and children aged 1-5 years (study 2, n = 173) to levocetirizine, 1.25 mg (q.d. or b.i.d., respectively), or placebo for 2 weeks, using a 2:1 ratio. Safety evaluations included treatment-emergent adverse events (TEAEs), vital signs, electrocardiographic (ECG) assessments, and laboratory tests. The overall incidence of TEAEs was similar between levocetirizine and placebo in both studies. Most TEAEs were mild or moderate in intensity. TEAEs prompted discontinuation of therapy in three patients receiving levocetirizine in study 1. No clinically relevant changes from baseline in vital signs or laboratory parameters were apparent in either study; changes from baseline in these evaluations were similar between groups. No significant changes were observed in ECG parameters, including corrected QT interval. Levocetirizine, 1.25 and 2.5 mg/day, was well tolerated in infants aged 6-11 months and in children aged 1-5 years, respectively, with AR or CIU.
Asunto(s)
Cetirizina/administración & dosificación , Antagonistas de los Receptores Histamínicos/administración & dosificación , Rinitis Alérgica Perenne/tratamiento farmacológico , Rinitis Alérgica Estacional/tratamiento farmacológico , Urticaria/tratamiento farmacológico , Administración Oral , Cetirizina/efectos adversos , Preescolar , Enfermedad Crónica , Progresión de la Enfermedad , Electrocardiografía , Femenino , Antagonistas de los Receptores Histamínicos/efectos adversos , Humanos , Lactante , Masculino , Rinitis Alérgica Perenne/diagnóstico , Rinitis Alérgica Perenne/fisiopatología , Rinitis Alérgica Estacional/diagnóstico , Rinitis Alérgica Estacional/fisiopatología , Resultado del Tratamiento , Urticaria/diagnóstico , Urticaria/fisiopatologíaRESUMEN
OBJECTIVE: To evaluate the efficacy of levocetirizine 5 mg once daily in reducing seasonal allergic rhinitis (SAR) symptoms in US adults. RESEARCH DESIGN AND METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study enrolled adults aged 18 to 65 years with SAR symptoms in the spring in the US. After a single-blind placebo run-in period, subjects received levocetirizine 5 mg or placebo once daily over 14 days. ClinicalTrials.gov registry no.: NCT00621959. MAIN OUTCOME MEASURES: Primary efficacy variable was the Total 5-Symptom Score (T5SS). Secondary variables included Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), Work Productivity and Activity Impairment-Allergy Specific (WPAI-AS) questionnaire, and Epworth Sleepiness Scale (ESS). Safety assessments were based on adverse events (AEs). RESULTS: The intent-to-treat population comprised 596 subjects (levocetirizine, n = 301; placebo, n = 295). Comparison of mean T5SS over the total treatment period showed a nonsignificant between-group difference (levocetirizine, 8.90 +/- 0.19; placebo, 9.04 +/- 0.19; adjusted mean difference, -0.14; p = 0.546). Levocetirizine showed numerical (mean RQLQ, WPAI-AS, ESS) and statistically superior differences (two domains within WPAI-AS) compared with placebo upon analysis of secondary efficacy variables. The incidence of treatment-emergent AEs was similar (levocetirizine, 23.9%; placebo, 24.4%). As the lack of efficacy was inconsistent with all previous levocetirizine studies, post hoc analyses were performed to assess the influence of pollen counts, geography, and other factors; however, no conclusive explanation could be identified. CONCLUSIONS: In this study, levocetirizine 5 mg QD was well tolerated but failed to show significant efficacy compared with placebo in a US adult population with SAR. This finding is inconsistent with all previous studies with levocetirizine and in contrast to a concurrently run, similarly designed US study. It reflects the importance of conducting duplicate studies as there is always a small but real risk of false negative results in clinical studies, irrespective of the methodologic quality.
Asunto(s)
Cetirizina/uso terapéutico , Antagonistas de los Receptores Histamínicos H1 no Sedantes/uso terapéutico , Rinitis Alérgica Estacional/tratamiento farmacológico , Adolescente , Adulto , Anciano , Cetirizina/farmacología , Método Doble Ciego , Femenino , Antagonistas de los Receptores Histamínicos H1 no Sedantes/farmacología , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Levocetirizine, a second-generation antihistamine for symptomatic treatment of allergic rhinitis and chronic idiopathic urticaria, has not been previously studied in US patients. OBJECTIVE: To assess the efficacy and safety of levocetirizine in improving symptoms and health-related quality of life in US adults with seasonal allergic rhinitis (SAR). METHODS: This multicenter, double-blind trial randomized adults with SAR, sensitized to at least 1 grass allergen, to receive levocetirizine, 5 mg, or placebo once daily in the evening for 2 weeks. The primary end point was the 24-hour reflective Total 5-Symptom Score (T5SS; sum of rhinorrhea, sneezing, nasal congestion, and nasal and ocular pruritus) during the entire treatment period. Secondary assessments included the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), Work Productivity and Activity Impairment-Allergy Specific (WPAI-AS) questionnaire, and Epworth Sleepiness Scale (ESS), each assessed at week 1, week 2, and the end of treatment. RESULTS: The intent-to-treat population comprised 287 patients taking levocetirizine and 290 taking placebo, with no significant between-group differences at baseline. Levocetirizine resulted in significantly greater improvement from baseline vs placebo in the T5SS (P < .001), overall RQLQ score (P < .001), general and work-related WPAI-AS subscores (P < .05), and ESS score (P < .001). Overall incidence of treatment-emergent adverse events was 14.4% for levocetirizine and 18.4% for placebo. The incidence of somnolence and fatigue was 0.7% and 1.8% with levocetirizine and 1.0% and 0% with placebo, respectively. CONCLUSIONS: Levocetirizine was well tolerated and was significantly more effective than placebo in improving the naso-ocular symptoms and health-related quality of life in US patients with SAR.
Asunto(s)
Cetirizina/uso terapéutico , Antagonistas de los Receptores Histamínicos H1 no Sedantes/uso terapéutico , Rinitis Alérgica Estacional/tratamiento farmacológico , Adolescente , Adulto , Anciano , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Placebos , Calidad de Vida , Resultado del Tratamiento , Estados UnidosRESUMEN
INTRODUCTION: The 505(b)(2) route of a New Drug Application (NDA) allows published literature or previous FDA findings of safety and effectiveness to be used for approval. Such drugs are not therapeutic equivalents (i.e., generics); instead, the FDA calls them pharmaceutical alternatives. A recent example is the approval of venlafaxine extended-release (ER) tablets, developed as an alternative to the widely used ER venlafaxine capsules. The smaller size of the tablets makes them available in a 225-mg strength, which is the approved maximum dose in major depressive disorder after up-titration but currently unavailable in the capsule formulation, requiring patients on this dose to take two or three capsules; in addition, the tablets are priced at a discount compared to the capsules. METHODS: The objective of this review was to investigate how the change in formulation of ER venlafaxine from capsules to tablets, as an example of such a change in formulation, can potentially offer value to patients and society, with a specific focus on pill burden, drug cost, and adherence. Based on a MEDLINE literature search, the pertinent literature was reviewed in a qualitative manner. REVIEW OF THE LITERATURE: Simplifying treatment regimens, reducing pill burden, and reducing drug costs are recognized strategies for improving adherence. This can be of particular benefit in psychiatric illness because of high rates of nonadherence to treatment. Lack of adherence may negatively impact treatment outcomes and increase disease cost. As such, the ER venlafaxine tablets have the potential to reduce pill burden, improve adherence and outcomes, and reduce cost to patients and society. These preliminary findings need to be corroborated with more primary research and a systematic review of formulation changes. CONCLUSION: A change in formulation of established therapies such as ER venlafaxine has the potential to offer clinical and pharmacoeconomic benefits to patients and society.
Asunto(s)
Ciclohexanoles/administración & dosificación , Composición de Medicamentos/economía , Composición de Medicamentos/métodos , Quimioterapia/economía , Ciclohexanoles/economía , Preparaciones de Acción Retardada/economía , Relación Dosis-Respuesta a Droga , Quimioterapia/métodos , Humanos , Modelos Biológicos , Estados Unidos , United States Food and Drug Administration/legislación & jurisprudencia , Clorhidrato de VenlafaxinaRESUMEN
BACKGROUND: Venlafaxine extended-release (ER) tablets use osmotic pressure to deliver venlafaxine hydrochloride at a controlled rate over approximately 24 hours. OBJECTIVE: These studies were conducted to evaluate the bioequivalence of venlafaxine ER tablets and capsules based on the US Food and Drug Administration (FDA) definition. METHODS: Four pharmacokinetic studies of the capsule (reference) and tablet (test) formulations were conducted in healthy adult volunteers. The first 2 were randomized, single-dose, 4-way crossover studies of either a 37.5-mg dose (study A) or a 75-mg dose (study B) of the reference and test products under fasting and fed conditions. The other 2 were randomized, 2-way crossover studies of either a single dose (study C) or multiple doses (study D) of venlafaxine ER 225 mg, delivered as one venlafaxine ER 225-mg tablet or one 150-mg + one 75-mg venlafaxine ER capsules under fed conditions. The primary outcome measures were the log-transformed C(max), AUC(0-t), and AUC(0-infinity). If the 90% CIs for the ratios of the least squares means of the primary outcome measures between the reference and test formulations fell within the regulatory range (80%-125%), the 2 formulations would be considered bioequivalent according to the FDA definition. RESULTS: Thirty-six subjects (21 men, 15 women; mean [SD] age, 28.0 [8.7] years; mean weight, 161.0 [26.0] lb) were enrolled in study A and completed all treatment periods. Thirty-six subjects were enrolled in study B, of whom 30 (22 men, 8 women; mean age, 33.5 [9.6] years; mean weight, 172.7 [23.9] lb) completed all treatment periods. Thirty-six subjects were enrolled in study C, of whom 28 (16 men, 12 women; mean age, 33.1 [12.9] years; mean weight, 160.6 [29.6] lb) completed the study. Thirty-four subjects were enrolled in study D, of whom 33 (29 men, 4 women; mean age, 26.0 [8.1] years; mean weight, 178.0 [30.3] lb) completed the study. In study A, the 90% CIs for the log-transformed ratio (test vs reference) of C(max), AUC(0-t), and AUC(0-infinity) in the fasted state were 95.58 to 107.48, 97.58 to 111.09, and 100.31 to 112.85, respectively; in the fed state, the corresponding values were 84.26 to 94.86, 93.49 to 106.58, and 98.98 to 111.91. In study B, the respective values in the fasted state were 113.07 to 126.10, 111.11 to 124.57, and 106.86 and 120.71; in the fed state, the values were 90.50 to 100.90, 96.80 to 108.50, and 95.05 to 107.21. In study C, fed values were 94.15 to 109.37, 103.8 to 115.85, and 102.64 to 113.39. In study D, which involved multiple doses, fed values for C(max) and AUC(0-t) were 82.26 to 88.77 and 101.16 to 109.45, respectively. Adverse effects included nausea, vomiting, dizziness, syncope, and somnolence. CONCLUSIONS: In these single- and multiple-dose studies, all doses of venlafaxine ER tablets tested met the FDA criterion for bioequivalence to the equivalent doses of venlafaxine ER capsules in the fed state. In the fasted state, the bioequivalence criterion was met for venlafaxine ER 37.5-mg tablets but not venlafaxine 75-mg tablets.
Asunto(s)
Antidepresivos de Segunda Generación/farmacocinética , Ciclohexanoles/farmacocinética , Adolescente , Adulto , Antidepresivos de Segunda Generación/administración & dosificación , Antidepresivos de Segunda Generación/efectos adversos , Área Bajo la Curva , Índice de Masa Corporal , Cápsulas , Estudios Cruzados , Ciclohexanoles/administración & dosificación , Ciclohexanoles/efectos adversos , Preparaciones de Acción Retardada , Humanos , Masculino , Persona de Mediana Edad , Comprimidos , Equivalencia Terapéutica , Clorhidrato de Venlafaxina , Adulto JovenRESUMEN
BACKGROUND: Trauma care is expensive. However, reliable data on the exact lifelong costs incurred by a major trauma patient are lacking. Discussion usually focuses on direct medical costs--underestimating consequential costs resulting from absence from work and permanent disability. METHODS: Direct medical costs and consequential costs of 63 major trauma survivors (ISS >13) at a Swiss trauma center from 1995 to 1996 were assessed 5 years posttrauma. The following cost evaluation methods were used: correction cost method (direct cost of restoring an original state), human capital method (indirect cost of lost productivity), contingent valuation method (human cost as the lost quality of life), and macroeconomic estimates. RESULTS: Mean ISS (Injury Severity Score) was 26.8 +/- 9.5 (mean +/- SD). In all, 22 patients (35%) were disabled, causing discounted average lifelong total costs of USD 1,293,800, compared with 41 patients (65%) who recovered without any disabilities with incurred costs of USD 147,200 (average of both groups USD 547,800). Two thirds of these costs were attributable to a loss of production whereas only one third was a result of the cost of correction. Primary hospital treatment (USD 27,800 +/- 37,800) was only a minor fraction of the total cost--less than the estimated cost of police and the judiciary. Loss of quality of life led to considerable intangible human costs similar to real costs. CONCLUSIONS: Trauma costs are commonly underestimated. Direct medical costs make up only a small part of the total costs. Consequential costs, such as lost productivity, are well in excess of the usual medical costs. Mere cost averages give a false estimate of the costs incurred by patients with/without disabilities.