Impact of Regulatory Interventions on Ulipristal Acetate 5 mg (Esmya) Use in Spain: An Interrupted Time-Series Analysis.

PURPOSE: Since late 2017, the use of ulipristal acetate 5 mg (UPA; Proprietary name: Esmya) has been under review in the European Union, due to an emerging hepatic risk. In February 2018 and in July 2018, the Spanish Agency of Medicines and Medical Devices and the marketing authorization holder put two risk minimization measures (RMM) in place, in order to inform about new safety information and to mitigate this risk. This study aims to assess RMM effectiveness in Spain, by performing an interrupted time-series (ITS) analyses, between 2014 and 2019. METHOD: Two quasi-experimental ITS analyses to examine the use of UPA before and after the RMM release were performed: (a) an ecological study using aggregated data from a drug consumption database; and (b) a study using primary healthcare data gathered from electronic clinical records. RESULTS: Regulatory interventions were associated with an immediate and significant decrease level of DID (the number of DDD dispensed per 100 000 inhabitants and day) and incidence. The DID was 70% less than expected 12 months after the interventions. This value was 59% for the incidence. However, a change in the slope was not observed and the use started rising again in the last segment of the study period. CONCLUSION: Despite RMM had an immediate strong impact on UPA use, the last segment upward trend in the long-term might have been affected by the lack of comparable therapeutic alternatives. Further studies should be performed to confirm the increase trend observed and analyze subsequent measures and additional data.

Emergency contraception - A narrative review of literature.

BACKGROUND: Emergency contraception includes several methods of contraception that can be used after unprotected sexual intercourse, after failure of any used method of contraception or in case of sexual abuse, to prevent pregnancy. PURPOSE OF THE STUDY: The aim of the study was to analyze the available methods of emergency contraception, their mechanisms of action, efficacy, forms of administration, clinical applications and possible adverse effects. MATERIAL AND METHOD: PubMed, Scopus and Cochrane datebases were searched for articles from 2010 to 2024 about emergency contraception. RESULTS: The analyzed types of emergency contraception included single oral dose of ulipristal acetate, single oral dose of levonorgestrel and intrauterine system releasing levonorgestrel or copper intrauterine device. Taking emergency contraception in the optimum time according to the drug characteristics allows for avoiding pregnancy in more than 90% of cases (depending on the type of emergency contraception and time from unprotected intercourse). The analyzed literature shows that intrauterine copper intrauterine device is the most effective method of emergency contraception, also together with intrauterine system releasing levonorgestrel leading to the lowest rate of adverse effects. CONCLUSIONS: Taking emergency contraception can result in various adverse effects, therefore it should be introduced after thorough analysis of woman's medical history, including gynecological and obstetric history and potential contraindications. Additionally, the patient should receive detailed information about the drug mechanism of efficacy and potential adverse effects.

Preliminary report of patients with meningiomas exposed to Cyproterone Acetate, Nomegestrol Acetate and Chlormadinone Acetate - Monocentric ongoing study on progestin related meningiomas.

INTRODUCTION: The relationship between meningioma and progestins has not been elucidated. Meningioma regression after acetate cyproterone (CA) withdrawal has been reported. Our purpose was to evaluate the meningioma evolution after withdrawal of progestins in patients who underwent long-term exposure to CA, nomegestrol acetate (NA), chlormadinone acetate (ChlA). METHODS: Our study retrospectively included 69 patients with intracranial meningioma and exposed to one of these 3 progestins between December 2006 and March 2019. In each patient, clinico-radiological (MRI) follow-up was performed every 6 months after diagnosis and treatment withdrawal recommendation. Statistical analyses were applied to compare tumor location and respect of prescription rules between the 3 groups. RESULTS: The mean hormonal exposure was 16 years in CA group (n = 46), 16 years in NA group (n = 12) and 9.7 years in ChlA group (n = 11). A higher rate of "out of label" use was observed in the CA group (p = 0.003). Multiple meningiomas were demonstrated in more than 60% of cases in each group. Anterior skull base location was noted in 60.5% of cases in CA group, 25% of cases in NA group and 36.7% of cases in ChlA group (p = 0.05). Incomplete tumor regression was recorded in 11 cases of CA group and in 2 cases of ChlA group. CONCLUSION: In CA group, our results suggest a strong relationship between this treatment and development of intracranial meningioma. In presence of voluminous asymptomatic meningioma, treatment can be delayed due to the potential regression after withdrawal. On the contrary in NA and ChlA groups, further studies are needed.

Acute liver failure requiring transplantation: A possible link to ulipristal acetate treatment?

The present case describes in detail a 55-year-old woman diagnosed with acute liver injury 3 days after completion of the first treatment course with ulipristal acetate (UPA), 5 mg/day orally for uterine fibroids causing persistent bleeding (treatment duration of 109 days). Liver transplantation was performed approximately 6 weeks after UPA suspension, and a photograph of the explanted liver is presented. Of note, other common causes of acute liver injury, such as history of alcohol or other psychoactive substances abuse, viral hepatitis and autoimmune hepatitis or preexisting liver disease were all excluded. This case was reported to the European Medicines Agency (EMA) and contributed to the final recommendations of the Pharmacovigilance Risk Assessment Committee (PRAC) disclosed in January 2021. The causality assessment considered a probable case of drug-induced liver injury as a consequence of UPA treatment, and the Roussel Uclaf Causality Assessment Method (RUCAM) was scored as unlikely. Although further studies are needed aiming to avoid confounding factors, this case suggests that liver function tests should be monitored during treatment with UPA.

Management of symptomatic uterine fibroids after ulipristal acetate suspension and identification of high risk patients for surgery at 6-months of follow-up.

OBJECTIVE: The use of ulipristal acetate (UPA) was indicated for the treatment of uterine fibroids. Following UPA suspension in March 2020, some patients presented worsening and required surgery. We aimed to identify patients at high-risk for undergoing surgery after UPA suspension. METHODS: We evaluated 85 women receiving intermittent UPA treatment until March 2020. Following UPA suspension, patients received other medical treatments or surgery. The clinico-pathological features were recoded and a quality of life health survey was completed by patients at the time of UPA suspension and at 6-months thereafter. RESULTS: After the suspension of UPA, 17 of the 85 patients receiving intermittent UPA (20%) required surgery, and 68 (80%) required other medical treatments. Patients who underwent surgery were younger and had greater fibroid volume. CONCLUSIONS: In our series, 20% of clinically stable patients receiving intermittent UPA required surgery following UPA suspension. These women should be considered for future medical strategies.

Pharmacokinetics, toxicological and clinical aspects of ulipristal acetate: insights into the mechanisms implicated in the hepatic toxicity.

Ulipristal acetate is a drug used as emergency contraceptive (30 mg) and for the treatment of moderate to severe symptoms of uterine myomas (5 mg). After commercialization, and although the exact number is unknown, serious cases implying ulipristal acetate 5 mg as a contributing factor of liver injury, some leading to transplantation, were reported. These cases prompted to a restrict use of the drug in January 2021 by the European Medicines Agency. This work aimed to fully review pharmacokinetic aspects, namely focusing in the ulipristal acetate metabolism and other hypothetical toxicological underlying mechanisms that may predispose to drug-induced liver injury (DILI). The high lipophilicity, the extensive hepatic metabolism, the long half-life of the drug and of its major active metabolite, the long-term course of treatment, and possibility due to the formation of epoxide reactive may be contributing factors. Scientific results also points evidence to consider monitorization of liver function during ulipristal acetate treatment.

Ulipristal acetate compared with leuprorelin acetate for Japanese women with symptomatic uterine fibroids: a phase III randomized controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of ulipristal acetate (UPA) for uterine fibroids (UFs), a phase III study was conducted with leuprorelin (LEU) as a comparator. This is the first confirmatory trial of UPA for UFs among Asians. DESIGN: Multicenter, randomized, double-blind, double-dummy, parallel-group study. SETTING: Thirty-two sites in Japan. PATIENT(S): Patients were assigned to 2 arms, with 82 patients in the UPA group and 79 patients in the LEU group. INTERVENTION(S): In the UPA group, 10 mg of UPA was orally administered once a day for 12 weeks. In the LEU group, 1.88 mg or 3.75 mg of LEU was subcutaneously administered at weeks 0, 4, and 8. MAIN OUTCOME MEASURE(S): The primary endpoint was the percentage of patients with amenorrhea for 35 days. For safety evaluation, adverse events (AEs) were recorded. RESULT(S): The percentage of patients with amenorrhea for 35 days was 87.0% in the UPA group and 81.8% in the LEU group, and the efficacy of UPA for causing amenorrhea for 35 days was confirmed to be noninferior to that of LEU. AEs occurred in 78.0% of the patients in the UPA group and 88.8% of the patients in the LEU group. CONCLUSION(S): The effect of UPA on heavy menstrual bleeding was shown to be comparable with that of LEU in Japanese patients with symptomatic UFs. No notable AEs occurred because of the UPA treatment, and the incidence of AEs in the UPA group was comparable with that of AEs in the LEU group. This result demonstrates the clinical utility of UPA for Asians.

Investigation of Inherited Chromosomally Integrated Human Herpesvirus-6A+ and -6B+ in a Patient with Ulipristal Acetate-Induced Fulminant Hepatic Failure.

Inherited chromosomally integrated (ici) human herpes virus 6 (HHV-6) is estimated to occur in 0.6-2.7% of people worldwide. HHV-6 comprises two distinct species: HHV-6A and HHV-6B. Both HHV-6A and HHV-6B integration have been reported. Several drugs are capable of activating iciHHV-6 in tissues, the consequences of which are poorly understood. We report herein a case of a woman with iciHHV-6A+ and iciHHV-6B+, who developed ulipristal acetate (a selective progesterone receptor modulator)-induced fulminant hepatic failure that required liver transplantation. We confirmed the presence of ~one copy per cell of both HHV-6A and HHV-6B DNA in her hair follicles using multiplex HHV-6A/B real-time PCR and demonstrated the Mendelian inheritance of both iciHHV-6A and iciHHV-6B in her family members over three generations. Because of the rarity of this presentation, we discuss herein the possible links between reactivated HHV-6 from iciHHV-6A and/or iciHHV-6B and adverse drug reactions, suggesting that iciHHV-6 could be screened before the introduction of any hepatotoxic drugs to exclude HHV-6 active disease or combined idiosyncratic drug-induced liver injury in these patients.

Local Transdermal Delivery of Telapristone Acetate Through Breast Skin, Compared With Oral Treatment: A Randomized Double-Blind, Placebo-Controlled Phase II Trial.

Oral breast cancer prevention medications entail systemic exposure, limiting acceptance by high-risk women. Delivery through the breast skin, although an attractive alternative, requires demonstration of drug distribution throughout the breast. We conducted a randomized double-blind, placebo-controlled phase II clinical trial comparing telapristone acetate, a progesterone receptor antagonist, administered orally (12 mg/day) or transdermally (12 mg/breast) for 4 ± 1 weeks to women planning mastectomy. Plasma and tissue concentrations, measured at five locations in the mastectomy specimen using liquid chromatography tandem mass spectrometry were compared. In 60 evaluable subjects, median drug concentration (ng/g tissue) was 103 (interquartile range (IQR): 46.3-336) in the oral vs. 2.82 (IQR: 1.4-5.5) in the transdermal group. Despite poor dermal permeation, within-breast drug distribution pattern was identical in both groups (R2  = 0.88, P = 0.006), demonstrating that transdermally and orally delivered drug is distributed similarly through the breast, and is strongly influenced by tissue adiposity (P < 0.0001). Other skin-penetrant drugs should be tested for breast cancer prevention.

Drug interactions between emergency contraceptive drugs and cytochrome inducers: literature review and quantitative prediction.

The emergency contraceptive drugs (EC), levonorgestrel (LNG) and ulipristal acetate (UPA), are sensitive substrates of cytochrome P450 3A4 (CYP3A4). In 2016, the label of LNG was updated based on a drug-drug interaction (DDI) study showing a significant decrease in LNG exposure when co-administered with efavirenz, a known CYP3A4 inducer. DDI between UPA and CYP3A4 inducers are poorly characterized. The aims of this study were to review quantitative data from the literature on DDI with EC, to provide quantitative predictions of DDI between UPA and CYP3A4 inducers, and to identify moderate and severe DDI that may require a dose adjustment. A literature search was performed on pharmacokinetic DDI of LNG and UPA. Quantitative prediction of DDI with UPA was carried out by using the in vivo mechanistic static model (IMSM). Limited information was available on DDI with emergency contraception drugs. For LNG, data from eleven studies were retrieved, including five known CYP3A4 inducers that confirmed a risk of underexposure to LNG when co-administered with inducers. For UPA, only three studies were identified, including only one CYP3A4 inducer. The IMSM approach indicated that UPA is a sensitive substrate of CYP3A4, with an estimated contribution of 86% of CYP3A4 to oral clearance. Moderate to severe DDI were predicted in 17 cases with CYP3A4 inducers, and dosage adjustments were suggested. This study illustrates the ability of the IMSM approach to inform about the DDI profile of old and new drugs.

Progression of adenomyosis magnetic resonance imaging features under ulipristal acetate for symptomatic fibroids.

RESEARCH QUESTION: What is the evolution of adenomyosis on magnetic resonance imaging (MRI) after a 3-month treatment course of daily 5 mg doses of ulipristal acetate (UPA) for symptomatic fibroids? DESIGN: A monocentric prospective pilot study on patients who underwent a 3-month treatment course of UPA for symptomatic fibroids between January 2014 and December 2017. Patients underwent pelvic MRI shortly before (pre-MRI) and after treatment (post-MRI). The diagnosis of adenomyosis on MRI was defined by the observation of intramyometrial cysts and/or haemorrhagic foci within these cystic cavities and/or a thickening of the junctional zone >12 mm. The progression of adenomyosis was defined by the presence of at least one of the aforementioned criteria of adenomyosis on the pre-MRI and by at least one of the following on the post-MRI: (i) increased thickness of the junctional zone ≥20% and/or (ii) increased number of intramyometrial cysts. The appearance of adenomyosis was defined by the absence of the aforementioned criteria of adenomyosis on the pre-MRI and the presence of at least one of these criteria on the post-MRI. RESULTS: Seventy-two patients were included. The MRI features of adenomyosis progressed for 12 of 15 patients (80.0%) for whom adenomyosis was identified on the pre-MRI. An appearance of adenomyosis was identified after treatment for 15 of 57 patients (26.3%) for whom adenomyosis was not identified on the pre-MRI. CONCLUSIONS: A 3-month treatment course of daily 5 mg doses of UPA could provoke a short-term progression or an emergence of typical adenomyosis intramyometrial cysts on MRI examinations.

Liver Injury with Ulipristal Acetate: Exploring the Underlying Pharmacological Basis.

INTRODUCTION: The European Medicines Agency has suspended the use of ulipristal acetate (UPA) in the treatment of uterine fibroids and is reassessing its association with a risk of liver injury. OBJECTIVES: Our objectives were to characterize the post-marketing reporting of drug-induced liver injury (DILI) with UPA and investigate the underlying pharmacological basis. METHODS: We queried the worldwide FDA Adverse Event Reporting System and performed a disproportionality analysis, selecting only hepatic designated medical events (DMEs) where UPA was reported as suspect. The reporting odds ratios (RORs) were calculated, and we considered a lower limit of the 95% confidence interval (LL95% CI) > 1 as significant. Physiochemical/pharmacokinetic features were extracted to assess the risk of hepatotoxicity by applying predictive DILI risk models. Mifepristone and leuprolide were selected as comparators. RESULTS: A significantly higher proportion of liver disorders was reported for UPA than for mifepristone (2.9 vs. 0.8%; p < 0.00001) and leuprolide (2.9 vs. 1.6%; p = 0.015). As regards hepatic DMEs, statistically significant RORs were found for autoimmune hepatitis (N = 5; LL95% CI 16.8), DILI (n = 5; LL95% CI 5.9), and acute hepatic failure (N = 5; LL95% CI 9.3). No signals of DILI emerged for mifepristone and leuprolide acetate. UPA and mifepristone showed high lipophilicity and hepatic metabolism (predicted intermediate DILI risk). Leuprolide exhibited contrasting features, resulting in no DILI concern. Inhibition of different liver transporters and the presence of a reactive metabolite were also recognised for UPA. CONCLUSION: Different drug properties previously linked to the occurrence of DILI may partially explain the reporting pattern observed with UPA. Our "bedside-to-bench" approach may support regulators in the risk-benefit assessment of UPA.

An Evaluation of Postmarketing Reports of Serious Idiosyncratic Liver Injury Associated with Ulipristal Acetate for the Treatment of Uterine Fibroids.

INTRODUCTION: Ulipristal acetate (ulipristal) is a selective progesterone receptor modulator that has been marketed for daily use in Europe and Canada to reduce symptoms caused by uterine fibroids. Long-term use of some other members of this class of 19-norprogesterone-derived agents has been associated with idiosyncratic hepatotoxicity. OBJECTIVE: We analyzed postmarketing reports of suspected drug-induced liver injury associated with the daily use of 5 mg of ulipristal to treat symptoms of uterine fibroids. METHODS: We searched for reports of serious liver injury associated with ulipristal, submitted to the US Food and Drug Administration through 31 January, 2020. Cases of liver injury temporally associated with long-term ulipristal exposure that reported combined increases of serum aminotransferases and bilirubin were individually assessed using a five-tier categorical scale of likelihood for a causal association with the drug by individuals with expertise in drug-induced liver injury evaluation. Individual cases that did not culminate in liver failure, death, or liver transplantation were also assessed for their causal association with ulipristal by the Roussel Uclaf Causality Assessment Method. RESULTS: We identified nine non-US cases that met the criteria for inclusion in our search for cases of serious liver injury associated with ulipristal. Five cases reported clinical outcomes of liver transplantation and/or death and all were assessed to have a probable causal association with ulipristal acetate. Evaluation of the other four cases reporting resolution of liver injury after treatment discontinuation revealed a possible or probable causal relationship with ulipristal. CONCLUSIONS: We identified postmarketing cases of serious acute drug-induced liver injury causally associated with ulipristal used to treat uterine fibroids, some with outcomes of liver transplant and/or death. The presence of common structural features identified with certain selective progesterone receptor modulators in the treatment of chronic conditions may indicate a liability for idiosyncratic drug-induced liver injury.

Suspension of ulipristal acetate for uterine fibroids during ongoing EMA's review of liver injury risk: Unfortunate timing during the Covid-19 pandemic!

OBJECTIVE: EMA decided that with ulipristal acetate (UPA) treatment for uterine fibroids, should be discontinued due to the associated risk of hepatic failure, We analyzed whether the risk of recurrent symptoms due to fibroids may lead to an increased risk of Covid -19 infection and death, that would exceed the former risk of hepatic failure and transplantation. STUDY DESIGN, SIZE, DURATION: We used a Markov model to generate probabilities. PARTICIPANTS/MATERIALS, SETTING, METHODS: There are currently about 36,250 treated patients in Europe. We estimated bleeding probabilities, while using or discontinuing UPA, which may induce a need of medical or surgical management in symptomatic patients, and increase the risk of acquiring a Covid-19 infection, and die from it. We also estimated the risk of suffering a hepatic failure and hepatic transplantation. MAIN RESULTS AND THE ROLE OF CHANCE: Based on our assumptions, ceasing UPA during a Covid 19 pandemic may be associated with a fatality ratio between 4 and 18, due to the Pandemic, whereas pursuing UPA would be associated with a fatality rate due to the pandemic between 1-2, and an added fatality rate due to hepatic impairment of 1. The added risk of stopping UPA may range between 2 and 15 additional deaths. Our calculations suggest that the decision to stop UPA in the middle of the Covid- 19 pandemic may be untimely, since it may result in an increased risk of Covid-19 infection, due to the recurrence of symptoms and the need for medical and surgical treatment. WIDER IMPLICATIONS OF THE FINDINGS: A decision, like the one EMA took need to be taken in a wider health context of a population, than simply analyzing its role as regulating agent for medications.

Management of symptomatic uterine fibroids with ulipristal acetate: A retrospective, multicentric and nationwide study.

OBJECTIVE: To evaluate symptomatic uterine fibroid outcomes following at least one course of ulipristal acetate (UPA) 5 mg/day therapy in the hospital setting, during the year 2017. STUDY DESIGN: A retrospective and descriptive analysis involving women with symptomatic fibroids was conducted in 15 hospital centers in Portugal in 2017 to assess fibroid size, bleeding control and hemoglobin levels following at least one course of UPA 5 mg/day. Secondary outcomes were the reasons for the treatment, type of surgery, fibroid classification, patient satisfaction with the treatment, and adverse events. RESULTS: Five-hundred and twenty-six patients were enrolled in this survey, and 93 % of the women completed, at least, 1 treatment course with UPA. Uterine bleeding control was achieved in 81 % of the cases. A significant increase (p < 0.001) in hemoglobin levels and a reduction (p < 0.001) in uterine fibroid size was observed after treatment, with a median reduction of 24 % from the baseline. Forty-seven percent of the patients underwent subsequent surgery and there were no serious adverse events reported in this multicentric nationwide study. CONCLUSIONS: So far, this is the largest case series reporting on symptomatic uterine fibroid outcomes after UPA therapy in Portugal. Our data are in line with published literature and confirm favorable outcomes after UPA therapy for women of childbearing age and premenopausal.

Efficacy and safety of vilaprisan in women with uterine fibroids: Data from the phase 2b randomized controlled trial ASTEROID 2.

OBJECTIVE: To assess the efficacy of vilaprisan compared with placebo in the management of the symptoms of uterine fibroids (UF), with a secondary objective to provide a descriptive comparison with ulipristal acetate. STUDY DESIGN: The randomized, parallel-group, double-blind, placebo- and active-controlled, multicenter ASTEROID 2 trial assessed the efficacy and safety of vilaprisan versus placebo and ulipristal acetate for two 12-week treatment periods in women with ≥1 UF experiencing heavy menstrual bleeding (HMB). The primary endpoint compared the efficacy of vilaprisan with placebo at 12 weeks, assessed as the absence of bleeding/spotting by bleeding diary. Secondary endpoints compared the efficacy of vilaprisan with ulipristal acetate. Results of the first 12-week treatment period are reported here. RESULTS: Women (mean age 42.5 years) were enrolled from 1 June 2015. At baseline, mean menstrual blood loss per 28 days was 214.1 mL and the volume of the three largest UF was 106.2 mL. In total, 155 women completed the initial 12-week treatment period. Complete absence of bleeding/spotting until the end of the 12-week treatment period was achieved by 62.9 % of women receiving vilaprisan versus 0.0 % with placebo (p < .001); 55.4 % of women treated with ulipristal acetate reported absence of bleeding/spotting. The predefined HMB response (<80 mL and >50 % reduction from baseline during the last 28 days of treatment) was observed in 95.7 % of subjects treated with vilaprisan and 86.5 % of subjects treated with ulipristal acetate. Vilaprisan and ulipristal acetate treatment reduced the sum of the volume of the three largest UF by 29.9 % and 23.8 %, respectively, whereas an increase of 6.3 % was observed in the placebo group. No safety concerns, including multiple laboratory parameters, were identified. CONCLUSION: Daily administration of vilaprisan 2 mg induced amenorrhea, controlled bleeding, decreased UF size, and was well tolerated in women with HMB associated with UF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number: NCT02465814 https://clinicaltrials.gov/ct2/show/NCT02465814.