RESUMO
BACKGROUND: Sodium oxybate (Xyrem®), approved by the European Medicines Agency (EMA) for narcolepsy with cataplexy, is only available through risk mitigation programs due to potential adverse effects including respiratory and central nervous system depression, neuropsychiatric events, and misuse. OBJECTIVE: We report findings from a survey evaluating effectiveness of the European Union Xyrem® Risk Management Plan (RMP). PATIENTS AND METHODS: A cross-sectional, online, multiple-choice survey was distributed to randomly selected healthcare professionals (HCPs) from six European countries (April 2016-May 2018). Eligibility criteria: current/potential Xyrem® prescriber and/or sleep disorder specialist; contact information available; on the Xyrem® RMP educational materials mailing list. PRIMARY OUTCOME: proportion of respondents answering each question correctly (< 50% responses correct = unsatisfactory comprehension, 50% to < 70% = satisfactory, ≥ 70% = excellent), with precision assessed using 95% confidence intervals (CIs). RESULTS: Of the 709 HCPs contacted, 601 did not agree to take part, 108 were screened with 35/108 eligible for inclusion; 31 HCPs completed the survey. Of the 31 respondents, 29 (93.5%; 95% CI 84.4-100.0) reported receiving Xyrem® safety information, commonly from a sales representative, EMA Summary of Product Characteristics (SmPC), or educational meeting; only 9/31 (31.0%; 14.3-50.0) recalled receiving mailed educational materials. The number of HCPs answering dosing-related questions correctly ranged from 24/31 to 31/31. All Xyrem® contraindications were correctly identified by 26/31 (83.9%; 70.0-96.7) respondents. All respondents 'always' or 'sometimes' completed SmPC recommended activities upon treatment initiation. The majority indicated signs of abuses/misuse/diversion (23/31; 74.2%; 58.6-88.0) and criminal use (23/31; 74.2%; 59.4-89.3) should be monitored at follow-up. CONCLUSIONS: These data demonstrate the importance of providing a range of educational materials. However, the low sample size limits interpretation; increased HCP engagement would improve understanding of how best to develop educational materials. EUROPEAN POST-AUTHORIZATION STUDY (PAS) REGISTER NUMBER: EUPAS15024.
RESUMO
Hydrocodone/chlorpheniramine is a prescription opioid licensed in the USA for the relief of cough and upper respiratory symptoms associated with allergy or cold in adults, previously contraindicated in children aged < 6 years. We present findings from a modern benefit risk review of hydrocodone/chlorpheniramine use as an antitussive agent in patients aged 6 to < 18 years. A cumulative search of the manufacturer's pharmacovigilance database covering 1 January 1900-7 August 2017 identified all individual case safety reports (ICSRs) associated with product family name "hydrocodone/chlorpheniramine." The search was inclusive of all MedDRA system organ classes, stratified by age (< 18 years). A comprehensive review of the scientific literature was conducted on safety and efficacy of opioids for pediatric treatment of cough. Three hundred and ninety-one ICSRs associated with hydrocodone/chlorpheniramine were identified; 35/391 ICSRs were in patients < 18 years of age; 18 were considered serious. Four fatalities were reported in patients 6 to < 18 years; two fatalities involved co-suspect medication azithromycin and two were poorly documented. Our literature search identified no robust efficacy data for hydrocodone/chlorpheniramine in the relief of cough and upper respiratory symptoms associated with allergy or cold in patients aged 6 to < 18 years. As we found no evidence of hydrocodone/chlorpheniramine efficacy in the pediatric population, we conclude that the benefit risk profile is unfavorable. This evidence contributed to the US Food and Drug Administration's (FDA's) recent decision that hydrocodone-containing cough and cold medications should no longer be indicated for treatment of cough in patients < 18 years, highlighting the value of proactive re-evaluation of the benefit risk profile of older established drugs. Plain Language Summary People often use medicines containing opioids to treat cough symptoms. The US Food and Drug Administration (FDA) recently decided that cough medicines containing opioids should not be used by children under 18 years old. Part of this decision was a review of the benefits and risks of using cough medicines that contain the opioid hydrocodone in children.Why was this review carried out? Most cough medicines that doctors can prescribe were approved several decades ago. Since then, rules for the approval of medicines have become stricter. In this review, researchers looked at the safety of hydrocodone, and how well this opioid relieves cough symptoms in children. Up-to-date information and modern research methods were used.The two key pieces of evidence found were: We could not locate any clinical trials providing robust evidence for the use of hydrocodone for cough relief in children under 18 years of age. (Outside the scope of this review, a number of clinical trials of hydrocodone-containing cough medicines in adults aged 18 years and over have shown the medicine to be effective in these patients.) Cough medicines containing opioids can cause harmful side effects in children such as breathing problems. In the research reported here, ten children died after taking a hydrocodone-containing cough medicine. Nine of these deaths were due to overdose. This evidence was used to draw the following conclusions: In children under 18 years of age, the risks of using hydrocodone for cough relief are greater than any benefits. Older medicines should be reviewed regularly to look at their safety and how well they are working using up-to-date evidence.
RESUMO
Study Objectives: To evaluate adherence to sodium oxybate prescribing information for indication and dosage, patients' compliance with instructions for use, safety/tolerability in routine clinical practice, and abuse potential. Methods: A postauthorization, noninterventional surveillance study (NCT00244465) in patients who were prescribed sodium oxybate according to current practice by sleep disorders specialists. Patients were monitored for ≤18 months. Results: Overall, 749 patients were enrolled; 730 included in the intent-to-treat population (narcolepsy type 1 n = 670, other indications n = 60). We report on patients with narcolepsy type 1 (female 47.9%, mean age 39.4 years); 495/670 (73.9%) completed the study. Median dose: at start of study 4.5 g per night, 6 g per night throughout study, in two equal doses. According to the treatment compliance checklist, 35.5 per cent of patients consumed alcohol, 19.3 per cent took the medication <2 hr after food, and 27.1 per cent did not adhere to recommended time schedule, with few associated treatment-emergent adverse events (TEAEs). Incidences of higher-than-recommended doses, difficulty in preparing doses, and abuse were low. TEAEs were reported by 67.3 per cent, most frequently headache (11.6%) and nasopharyngitis (6.4%). Discontinuation due to TEAEs: 8.8 per cent. Serious TEAEs: 6.4 per cent. There were no reports of respiratory depression. No particular safety concerns were identified in pediatric or elderly patients, or those with underlying sleep apnea. Conclusions: In this large postauthorization safety study of sodium oxybate use, indication and dosage prescribing recommendations were generally followed, and most patients complied with instructions, with deviations around alcohol consumption, eating before dosing and timing. The overall safety profile was consistent with previous observations; incidence of abuse was low. Section: Neurological disorders. Clinical Trial: Postauthorization, noninterventional, surveillance, pharmacoepidemiology study to evaluate long-term safety, tolerability, and compliance in administration of Xyrem (sodium oxybate) oral solution in patients who receive treatment with this medication in regular clinical practice. https://clinicaltrials.gov/ct2/show/NCT00244465, ClinicalTrials.gov: NCT00244465.
Assuntos
Anestésicos Intravenosos/uso terapêutico , Adesão à Medicação , Narcolepsia/tratamento farmacológico , Narcolepsia/epidemiologia , Vigilância da População , Oxibato de Sódio/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Narcolepsia/diagnóstico , Vigilância da População/métodos , Resultado do TratamentoRESUMO
Managing symptoms of allergic rhinitis (AR) and urticaria in pregnant women is important to reduce complications and negative outcomes. The objective of this study was to provide information on the pregnancy outcomes of women exposed to the antihistamine cetirizine (CTZ). The UCB Pharma Patient Safety Database was searched for pregnancies up to 28 February 2015. Maternal CTZ exposure reports were extracted, and pregnancy outcomes were examined, including exposure, comorbidities and infant events. 228 of 522 pregnancies with maternal CTZ exposure had available outcomes; 49 were prospective. The majority (83.7%) resulted in live births; four spontaneous miscarriages, three induced abortions and one stillbirth were reported. Most pregnancies were exposed during the first trimester. Two congenital malformations were reported. The results suggest that CTZ exposure is not associated with adverse pregnancy outcomes above the background rates. While reassuring, the strengths and limitations of a safety database study need to be considered. Impact statement What is already known on this subject? AR and urticaria can substantially affect pregnant women, and adequately managing their symptoms is important to reduce maternal and foetal complications. Antihistamines are efficacious, however, there is still a lack of data regarding use during pregnancy. Although current evidence indicates that antihistamines are well-tolerated during pregnancy, data regarding foetal safety are inconclusive. What do the results of this study add? Our study suggests that CTZ exposure during pregnancy is not linked to an increase in adverse outcomes. CTZ exposure mainly happened during the first trimester only, when most organogenesis takes place. Most of the maternally exposed, prospective pregnancies resulted in live births (83.7%). Congenital malformations occurred in 2/41 live births from the CTZ-exposed pregnancies. What are the implications of these findings for clinical practice and/or further research? Our study presents a detailed data analysis from a large number of CTZ-exposed pregnancies, and its results are in line with those from previous reports. While the limitations of a safety database study need to be considered, the results shown here are reassuring. Further prospectively reported pregnancies are required, before definite conclusions on the risks of CTZ exposure during pregnancy can be drawn.
Assuntos
Antialérgicos/efeitos adversos , Cetirizina/efeitos adversos , Resultado da Gravidez/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Rinite Alérgica/tratamento farmacológico , Adulto , Bases de Dados Factuais , Feminino , Humanos , Exposição Materna/estatística & dados numéricos , Gravidez , Estudos Prospectivos , Estudos RetrospectivosAssuntos
Alprostadil/administração & dosagem , Assistência Ambulatorial , Claudicação Intermitente/tratamento farmacológico , Pentoxifilina/administração & dosagem , Vasodilatadores/administração & dosagem , Administração Intravenosa , Administração Oral , Alprostadil/efeitos adversos , Método Duplo-Cego , Tolerância ao Exercício/efeitos dos fármacos , Humanos , Claudicação Intermitente/diagnóstico por imagem , Claudicação Intermitente/fisiopatologia , Medição da Dor , Pentoxifilina/efeitos adversos , Estudos Prospectivos , Qualidade de Vida , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do Tratamento , Vasodilatadores/efeitos adversos , CaminhadaRESUMO
Several noncardiac drugs have been linked to cardiac safety concerns, highlighting the importance of post-marketing surveillance and continued evaluation of the benefit-risk of long-established drugs. Here, we examine the risk of QT prolongation and/or torsade de pointes (TdP) associated with the use of hydroxyzine, a first generation sedating antihistamine. We have used a combined methodological approach to re-evaluate the cardiac safety profile of hydroxyzine, including: (1) a full review of the sponsor pharmacovigilance safety database to examine real-world data on the risk of QT prolongation and/or TdP associated with hydroxyzine use and (2) nonclinical electrophysiological studies to examine concentration-dependent effects of hydroxyzine on a range of human cardiac ion channels. Based on a review of pharmacovigilance data between 14th December 1955 and 1st August 2016, we identified 59 reports of QT prolongation and/or TdP potentially linked to hydroxyzine use. Aside from intentional overdose, all cases involved underlying medical conditions or concomitant medications that constituted at least 1 additional risk factor for such events. The combination of cardiovascular disorders plus concomitant treatment of drugs known to induce arrhythmia was identified as the greatest combined risk factor. Parallel patch-clamp studies demonstrated hydroxyzine concentration-dependent inhibition of several human cardiac ion channels, including the ether-a-go-go-related gene (hERG) potassium ion channels. Results from this analysis support the listing of hydroxyzine as a drug with "conditional risk of TdP" and are in line with recommendations to limit hydroxyzine use in patients with known underlying risk factors for QT prolongation and/or TdP.
RESUMO
BACKGROUND: There are limited data on the use of the antiepileptic drug (AED) levetiracetam for the treatment of infants. AIM: To prospectively evaluate the safety of levetiracetam oral solution and its impact on epilepsy severity in infants with different seizure types. METHODS: This noninterventional post-authorization safety study included patients 1-11 months of age. Patients' treatment - levetiracetam dose, and addition, withdrawal or changes in the doses of concomitant medications and AEDs - was at the discretion of the physician. The primary variable was treatment-emergent adverse events (TEAEs). RESULTS: Of 101 infants, 75 completed and 26 discontinued the study. Mean age was 6.0 months, 50 were male, most (80%) took 1 ≥ concomitant AED and had cryptogenic or symptomatic epilepsy that was focal (38.6%) or generalized (20.8%), particularly frontal lobe epilepsy (20.0%) or West syndrome/infantile spasms (20.0%). Among known aetiologies, congenital factors (22.8%) such as dysplastic lesions or perinatal events (17.8%) were predominant. Overall, 54.5% of patients had ≥ 1 TEAE. Five patients experienced drug-related TEAEs - convulsion, irritability, somnolence and hypotonia, all listed in the product label, with the exception of hypotonia, which was reported for one patient and resolved without any change in study medication. Seven patients discontinued due to TEAEs, mainly due to infantile spasms and respiratory disorders. At study end, 71.8% of patients showed improvement in epilepsy severity, 18.8% remained stable and 9.4% showed worsening. Levetiracetam did not appear to have a negative effect on growth parameters. CONCLUSION: In this prospective study, which included the largest number of patients in this age range so far, levetiracetam was found to be well tolerated and efficacious for the treatment of infants with epilepsy.
Assuntos
Anticonvulsivantes/farmacologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Epilepsia/tratamento farmacológico , Piracetam/análogos & derivados , Anticonvulsivantes/efeitos adversos , Europa (Continente) , Feminino , Humanos , Lactente , Levetiracetam , Masculino , Piracetam/efeitos adversos , Piracetam/farmacologia , Estudos Prospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: This study was performed to compare the pharmacokinetic properties and relative bioavailability of two isosorbide-5-mononitrate (5-ISMN) sustained-release drugs in healthy Korean subjects under fasting and fed conditions. METHODS: A total of 60 healthy volunteers (30 each in the fasting and fed arms of the study) were enrolled in the study and were randomized to treatment. After the administration of a single dose of one of the investigational products, blood samples were collected at specific time intervals from 0 to 36 hours. The plasma concentrations of 5-ISMN were measured by LC-MS/MS. The pharmacokinetic parameters were calculated, and the 90% confidence intervals (CIs) of the geometric mean ratio (test/reference) of the parameters were obtained by analysis of variance on logarithmically transformed data. RESULTS: The corresponding 90% CIs of AUClast and Cmax for the test/reference geometric mean ratio were 90.75 - 98.44% and 92.28 - 98.33%, respectively, under fasting conditions. In the fed state study, the 90% CIs for the geometric mean ratio of test to reference drugs were 94.79 - 103.33% for AUClast and 99.86 - 108.02% for Cmax. CONCLUSION: The test product is equivalent to the reference product in subjects under fasting and fed conditions within the Korean regulatory bioequivalence criteria. Both formulations were safe and well tolerated, and there were no noteworthy differences in the safety profiles between the test and reference drugs.