RESUMEN

INTRODUCTION: Nirogacestat is a targeted gamma secretase inhibitor approved in the United States for adults with progressing desmoid tumors. In the phase 3 DeFi study (NCT03785964) of nirogacestat, ovarian toxicity (OT) was identified as a safety signal among females of reproductive potential (FORP). This analysis further describes the incidence, presentation, and resolution of OT. METHODS: Patients were randomized to twice-daily oral nirogacestat (150 mg) or placebo, taken in continuous 28-day cycles. Investigator-identified OT in FORP was based on abnormal reproductive hormone values or perimenopausal symptoms (or both). Adverse event follow-up was conducted to assess OT resolution. Post hoc analyses included return of menstruation and return of follicle-stimulating hormone (FSH) to within normal limits (WNL) (≤20.4 mIU/mL). RESULTS: Of 92 randomized females, 73 in the safety population were FORP (n = 36 nirogacestat, n = 37 placebo). OT was identified in 75% (27 of 36) receiving nirogacestat and 0% (0 of 37) receiving placebo. As of October 24, 2022, investigators reported OT resolution in 78% (21 of 27) of patients, with median OT duration of 19.1 weeks. Off-treatment resolution was reported in all 11 patients (100%) who stopped nirogacestat treatment; of these, all nine with available menstruation information experienced return of menstruation and eight had FSH WNL at last reported assessment. Resolution was reported in 10 of 14 (71%) while on nirogacestat; of these, all 10 experienced return of menstruation and seven had FSH WNL. Two patients were lost to follow-up. CONCLUSION: Most FORP treated with nirogacestat experienced OT, with the majority resolving, including all who stopped treatment, suggesting that OT is transient.

Asunto(s)

RESUMEN

AIM: To describe the antiseizure medications (ASMs) prescription pattern in women of childbearing age (WOCA) and pregnant women with epilepsy in the 2019-2022 period in Poland MATERIALS AND METHODS: The National Health Fund (NHF) databases were analyzed. Women aged 15-49 years were considered as being of childbearing age, while exposure during pregnancy was estimated taking into account 15 months before delivery. ASMs belonging to the N03A subgroup of the Anatomical Therapeutic Chemical Classification System, reimbursed by NHF were analyzed. RESULTS: During 2019, 36 784 WOCA and 921 pregnant women filled at least 1 ASM prescription. In 2022, these numbers were 32 304 and 594, respectively. Valproate was the most widely used ASM in WOCA (38.4 %) in 2019, followed by levetiracetam (35.6 %), lamotrigine (30.1 %), and carbamazepine (20.0 %). The percentage of ASM users decreased in 2022 for valproate (32.1 %; p < 0.001) and carbamazepine (17 %; p < 0.001) and increased for levetiracetam (40.8 %; p < 0.001) and lamotrigine (32.7 %; p < 0.001). In 2019 lamotrigine (42.1 %) and levetiracetam (41.5 %) were the most frequently prescribed ASMs to pregnant women. During the study period, a significant increase in prescriptions for levetiracetam was observed (49.5 %; p = 0.003). The proportion of ASMs exposed pregnancies declined for valproate (from 24.7 to 16 %; p < 0.001) and topiramate (from 6.6 to 3.2 %; p = 0.005). The percentage of polytherapy regimens remained stable over the years, both for WOCA (39 %) and pregnant women (32 %). CONCLUSION: Despite the decline in valproate usage, the drug was still among the most commonly prescribed ASMs in women of childbearing age and pregnant women with epilepsy. The awareness of teratogenic risks and new treatment guidelines should be improved in Poland.

Asunto(s)

RESUMEN

Introducción: En 2015 se aplicaron en España distintas medidas para la minimización de los riesgos (MMR) del ácido valproico. Objetivo: El objetivo de este estudio es evaluar la eficacia de las MMR del ácido valproico en España, con el fin de reducir el uso de ácido valproico como terapia de primera línea y evaluar los patrones de prescripción de ácido valproico en las mujeres, incluidas las mujeres en edad fértil (MEF), en los períodos previos y posteriores a la implementación de las MMR. Materiales y métodos: Los patrones de prescripción del ácido valproico en mujeres y MEF antes y después de la implementación de las MMR se examinaron utilizando la base de datos longitudinales de pacientes (longitudinal patient data, LPD por sus siglas en inglés), que incluye información de pacientes de dos paneles: médicos de atención primaria (MAP) y neurólogos/psiquiatras. El criterio principal de valoración fue la proporción de prescripciones iniciales de ácido valproico con al menos un medicamento relacionado con indicaciones de ácido valproico antes de la fecha de inicio del ácido valproico. Resultados: La proporción de prescripciones de ácido valproico secundarias con uso previo de medicamentos relacionados con indicaciones de ácido valproico fue del 78% –intervalo de confianza (IC) al 95%: 73,9-81,5%– y del 78,2% (IC al 95%: 74,5-81,4%) en los períodos principales previo y posterior a la implementación en el panel de MAP. Las cifras correspondientes a MEF fueron del 79,6% (IC al 95%: 73,6-84,5%) y del 75,5% (IC al 95%: 69,7-80,6%), respectivamente. La tasa de incidencia de embarazos expuestos al ácido valproico (por 1.000 personas-años) en MEF disminuyó de 17,4 en el período completo previo a la implementación a 8,5 en el período completo posterior a la implementación...(AU)

Introduction: Risk minimisation measures for valproate were implemented in Spain in 2015.Objective: The objective of this study is to assess the effectiveness of valproate risk minimisation measures in Spain intended to decrease the use of valproate as a first-line therapy, and to evaluate the prescribing patterns of valproate in women, including women of childbearing potential, in the pre- and post-implementation risk minimisation measures periods. Materials and methods: The prescribing patterns of valproate in females and women of childbearing potential before and after risk minimisation measures implementation were examined using the longitudinal patient data database, which includes patient information from two panels: primary care physicians and neurologists/psychiatrists. Primary endpoint was the proportion of initial valproate prescriptions with at least one medication related to the valproate indications before the valproate initiation date. Results: The proportion of incident valproate prescriptions with previous use of medication related to valproate indications was 78.0% (95% CI, 73.9%; 81.5%), and 78.2% (74.5%; 81.4%) in the main pre-and post-implementation periods in the primary care physician panel. The corresponding figures for women of childbearing potential were 79.6% (73.6%; 84.5%) and 75.5% (69.7%; 80.6%), respectively. The incidence rate of pregnancies exposed to valproate (per 1,000 person-years) in women of childbearing potential decreased from 17.4 the entire pre-implementation to 8.5 in the entire post-implementation periods. Conclusion: After the implementation of risk minimisation measures for valproate in Spain, no meaningful change in prescribing was observed regarding the proportion of valproate initiations preceded by prior medication related to valproate indications. The preventative measures recommended for use of valproate in women of childbearing potential should be considered.(AU)

Asunto(s)

RESUMEN

BACKGROUND: In the era of rapid dolutegravir rollout, concerns about neural tube defects have complicated the health systems response among women of childbearing potential. This qualitative study, which was nested within the DolPHIN-2 clinical trial, examined the current and future health system opportunities and challenges associated with the transition to dolutegravir-based regimen as first line antiretroviral therapy among women of childbearing potential in South Africa and Uganda. METHOD: Semi-structured in-depth interviews with members of antiretroviral therapy guideline development groups and affiliates were conducted. Thirty-one participants were purposively selected for the study, including senior officials from the Ministry of Health and National Drug Regulatory Authority in Uganda and South Africa as well as health-sector development partners, activists, researchers and health workers. A thematic approach was used to analyse the data. FINDINGS: Despite differences in health system contexts, several common challenges and opportunities were identified with the transition among women of childbearing potential in South Africa and Uganda. In both contexts national stakeholders identified challenges with ensuring gender equity in roll out due to the potential teratogenicity of dolutegravir, paucity of data on dolutegravir use in pregnancy, potential stock out of effective contraceptives, poorly integrated contraception services, and limited pharmacovigilance in pregnancy. Participants identified opportunities that could be harnessed to accelerate the transition, including high stakeholder interest and commitment to transition, national approval and licensure of a generic tenofovir/lamivudine/dolutegravir regimen, availability of a network of antiretroviral therapy providers, and strong desire among women for newer and more tolerable regimens. CONCLUSION: The transition to dolutegravir-based regimens has the potential to strengthen health systems in low- and middle-income countries to engender equitable access to optimised antiretroviral regimen among women. There is the need for a multi-sectoral effort to harness the opportunities of the health systems to addresses the bottlenecks to the transition and initiate extensive community engagement alongside individual and institutional capacity strengthening. Improvements in pregnancy pharmacovigilance and counselling and family planning services are critical to ensuring a successful transition among women of childbearing potential.

Asunto(s)

RESUMEN

Genetic or idiopathic generalized epilepsies (IGEs) account for 15-20% of all epilepsies. These syndromes have always been considered as good prognosis forms of epilepsy over time; however, for some patients, there is a need to maintain antiseizure drugs (ASD) for a long-time. Drug resistance is not uncommon (7-15%). Lifestyle remains essential and is an integral part of the treatment. Comorbidities such as obstructive sleep apnea syndrome must be considered and treated. A highly underestimated condition is the risk of sudden unexpected death in epilepsy (SUDEP). Very few data are available about the prevalence of SUDEP in IGE, but patients with generalized tonic-clonic seizures (GTCS) are exposed to this risk. IGEs are also characterized by a specific pharmalogical sensisitivity but may be aggravated by ASDs. Historically, the treatment of IGEs has relied mostly on valproate but this drug should be avoided in women of childbearing potential. Women with IGE not treated with valproate are more likely to have unsatisfactory seizure control. Female gender appears now as a new risk factor for drug-resistance. Finally, aside from the typical forms, there are epilepsies that fulfill most of the criteria of IGE, but that have an unusual history with GTCS, absences, falls, and drug resistance. Patients do not have psychomotor regression, brain magnetic resonance imaging is normal. EEG shows generalized fast rhythms during NREM sleep. These patients with refractory generalized epilepsy with sleep-related fast activities do not belong to a well-established syndromic category. These cases are considered "intermediary" between IGE and epileptic encephalopathies.

Asunto(s)

RESUMEN

BACKGROUND/AIMS: The Clinical Trials Coordination and Facilitation Group has issued recommendations on contraception and pregnancy testing to help sponsors meet regulatory expectations and harmonize practices to limit embryofetal risks in clinical trials. Our objective was to assess the compliance of French academic clinical trials with these recommendations and to describe the mitigation measures required by sponsors in their trials. METHODS: A cross-sectional study was performed on the French academic drug trials authorized by the national competent authority between January 2015 and June 2018. We included trials which tested systemic administration of drugs and enrolled men or women of childbearing potential. RESULTS: Data from 97 trials included were compiled. One-third of the trials (23.8%-43.3%, 95% confidence interval) complied with the Clinical Trial Facilitation and Coordination Group recommendations. No improvement over time or according to embryofetotoxic status or drug duration exposure was found. Contraception was required in 56.7% of trials and was more often required in case of potentially embryofetotoxic drugs (68.5% vs 41.9%, p = 0.013) or exposure over 1 month (71.7% vs 43.8%, p = 0.006). Pregnancy testing at inclusion was required in 59.1% of trials and additional testing in 17.2%. Pregnancy testing at inclusion was more often required in trials with drug exposure above 1 month (67.4% vs 45.8%, p = 0.035). CONCLUSION: French academic sponsors barely met the recommendations on contraception and pregnancy testing potentially leading to potential embryofetal risks in case of pregnancy. They need to implement these recommendations quickly.

Asunto(s)