Safety and tolerability of a combined oral contraceptive containing estetrol/drospirenone in real-life clinical practice: An open-label, prospective, multicenter, epidemiological, observational program "Estetiko"

This article presents the results of the prospective study involving 70 patients of reproductive age with heavy menstrual bleeding (HMB) and dysmenorrhea, interested in reliable contraception. Objective. To study the safety and efficacy of the low-dose combined oral contraceptive (COC) containing chlormadinone acetate (CMA) for the treatment of dysmenorrhea and HMB in real clinical practice. Patients and methods. Among 90 women who sought a method of contraception, we identified a group of 70 patients aged 18–45 years (mean age = 31.0 ± 7.7 [95% CI 29.2–32.9]) with complaints for HMB (n = 23) and/or dysmenorrhea (n = 65): primary (n = 37) and secondary (n = 28). For contraception, COC containing 0.03 mg ethinyl estradiol and 2 mg CMA was recommended. After 3 months, the dynamics of the volume of menstrual blood loss, pain severity (according to the Numeric Rating Scale (NRS)), as well as the frequency of side effects were assessed. Results. Among 90 women of reproductive age, 70 (78%) had HMB and/or dysmenorrhea of varying severity. After 3 months of using a low-dose CMA-containing COC, 87% of patients with HMB showed a statistically significant decrease in menstrual blood loss (p < 0.001); in 72% of patients, a significant decrease in pain severity was observed: mean NRS value before taking COC was 6.2 ± 2.1 [95% CI 5.7–6.7]), it decreased to 3.5 ± 1.8 [95% CI 3.0-3.9]) (p < 0.001) after 3 months. There were no significant differences in efficacy between the groups with primary and secondary dysmenorrhea. Conclusion. The prevalence of HMB and dysmenorrhea in a random sample of women of reproductive age is consistent with the data of systematic reviews (26% and 72%, respectively). The results obtained in real clinical practice confirm the additional therapeutic efficacy of the low-dose CMA-containing COC in HMB and dysmenorrhea. The frequency and severity of side effects during the COC use do not depend on the initial body mass index, but with an increase in the waist-to-hip ratio, there is a tendency to reduce the chance of developing side effects of using COC, which corresponds to the data on the metabolic neutrality of chlormadinone. Key words: chlormadinone, heavy menstrual bleeding, dysmenorrhea

Co-administration of combined oral contraceptives and psychotropic drugs: risk of contraceptive failure and adverse events.

The review presents the psychosocial characteristics of young women in todays millennial generation and survey data regarding their hormonal contraceptive requirements. The results of randomized clinical trials and real-life studies of the use of the combined oral contraceptive (COC) Qlaira containing estradiol valerate and dienogest (E2V/DNG) in a dynamic dosing regimen were analyzed, in which the reliability of the contraceptive effect of the drug was identified and confirmed, the restoration of fertility was population level after drug withdrawal, its minimal effect on metabolism and a reduced risk of cardiovascular complications (venous and arterial thrombosis) when using Qlaira COC in comparison with other COCs. The absence of a negative effect of COC E2V/DNG on body weight, sexual function and vaginal microbiocenosis in most women has been proven. The data on satisfactory characteristics of menstrual bleeding (lighter and shorter) in users of Qlaira COC and a decrease in symptoms associated with a hormone-free interval, which often occur when taking other COCs in the 21/7 regimen, are presented. The favorable efficacy and safety profile of COC E2V/DNG in real conditions, the advantages of estrogen bioidentical to the endogenous, in the composition of the drug, the dosage regimen 26/2, the positive effect on the lifestyle, determine the significant satisfaction of young women, including young women with children, and the ability to use the drug for a long time until menopause.

Body mass index does not affect the efficacy or bleeding profile during use of an ultra-low-dose combined oral contraceptive

Psoriatic arthritis (PsA) is a chronic immunoinflammatory disease of the joints, spine and entheses from the group of spondyloarthritis, which is usually observed in patients with psoriasis. In recent years, the axial form of PsA (axPsA) has been actively researched. However, there is insufficient data on approaches to the diagnosis and treatment of patients with axPsA in real-life clinical practice. This article presents the results of an interim analysis of data from a non-interventional multicenter observational study on the treatment of patients with axPsA in real-life clinical practice (NiSaXPA) in Russian centers.Objective: to identify patients with axPsA, their characteristics and describe treatment tactics in real-life clinical practice.Material and methods. Patients with PsA who met the inclusion criteria were prospectively followed up during routine visits to a rheumatologist. Participants' axial radiographs were uploaded to a database in order for it to be confirmed the presence or absence of axPsA by two independent experts, a rheumatologist and a radiologist. Patients with a confirmed axPsA diagnosis participated in a further data collection phase (Visit 2, week 24).Results and discussion. Six hundred patients were enrolled into the study. At the time of analysis, 386 (64.3%) of them (209 men and 177 women) were screened for axPsA. The diagnosis of axPsA was confirmed in 241 (62.4%) cases; these patients formed the Per Protocol (PP) population. The mean age of patients with axPsA in the PP population was 46.30±12.6 years and the body mass index (BMI) was 27.4±5.2 kg/m2 . In 14.9% of patients, the duration of psoriasis was less than 1–5 years, in 21.5% – 5–10 years and in 63.6% – more than 10 years. The duration of PsA symptoms was less than 1–5 years in 31.2 % of patients, 5–10 years in 31.6 % and more than 10 years in 37.2 %. Low disease activity (BASDAI ˂ 4) was achieved in 33.3 % of patients with axPsA at visit 1 and in 64.3 % at visit 2; the BASDAI index declined on average from 4.67±1.95 to 3.31±1.89 points.In real-life clinical practice, patients were most frequently prescribed non-steroidal anti-inflammatory drugs (NSAIDs) – 88.7% and 71.7% (visits 1 and 2, respectively), and synthetic disease-modifying antirheumatic drugs (sDMARDs) –79.1% and 70.7%, respectively; therapy with biologic disease-modifying antirheumatic drugs (bDMARDs) was initiated in 40.2% and 60.6% of patients, respectively.Conclusion. The results of the interim analysis of this observational study showed that in 87.2% of patients who met the CASPAR criteria for PsA there was a suspicion of axial manifestations of PsA on the primary care level. However, only 62.4% of them had a confirmed diagnosis of axPsA on centralized expert assessment, which may indicate a possible overdiagnosis of axial lesions in real-life practice and emphasizes the importance of collaboration between a rheumatologist and a radiologist when analyzing the results of imaging studies. 33.3% of patients with axPsA had low disease activity according to BASDAI at baseline and 64.3% after 24 weeks, meaning that the disease was only adequately controlled in one third of cases despite therapy; the number of these patients doubled after a change in therapy. In real-world clinical practice, patients with axPsA are most commonly prescribed drugs from the NSAID and sDMARD groups; the frequency of use of biologic drugs varied between 40.2 and 60.6% by the end of the observation period.

This letter to the editor addresses the concern regarding women who are HIV positive and interested in oral contraceptives. HIV positive women are typically advised to avoid using combined oral contraceptives which proves difficult because COC’s are the most widely circulated contraceptives in the world. Health care professionals must understand the pharmacokinetics and pharmacodynamics between COC pills and ART treatments. This is especially important in areas with high rates of HIV positive women or where rates exceed 10% HIV positive females within the HIV population. In these areas women should be informed of the most effective treatment for their unique condition.

Background:While combined oral contraceptives (COCs) are commonly used to treat polycystic ovary syndrome (PCOS), comparative data regarding metabolic effects of different progestogens on this patient population are missing. This study aimed to compare the different effects of drospirenone (DRP)-containing COCs with cyproterone acetate (CPA)-containing COCs, combined with metformin and lifestyle modifications in women with PCOS and metabolic disorders.Methods:Ninety-nine women with PCOS and a metabolic disorder between January 2011 and January 2013 were enrolled into this prospective randomized clinical trial. Participants were randomized into two groups such as DRP-containing COCs, and CPA-containing COCs. Participants took COCs cyclically for 6 months, combined with metformin administration (1.5 g/d) and lifestyle modifications (diet and exercise). Clinical measures and biochemical and hormone profiles were compared. Comparisons for continuous variables were evaluated with paired and unpaired Student's t-tests. The Wilcoxon signed rank test was used when the data were not normally distributed. Analysis of covariance was used to control for age, body mass index (BMI), and baseline data of each analyzed parameter when compared between the two groups.Results:A total of 68 patients have completed the study. The combination regimen of COCs, metformin, and lifestyle modifications in these patients resulted in a significant decrease in BMI, acne, and hirsutism scores when compared to baseline levels in both groups (P < 0.05). Blood pressure (BP) was significantly different in the CPA group when compared to baseline (75.14 ± 6.77 mmHg vs. 80.70 ± 5.60 mmHg, P < 0.01), and after 6 months of treatment, only the change in systolic BP was significantly different between the two groups (4.00 [–6.00, 13.00] mmHg vs. –3.50 [–13.00, 9.00] mmHg, P = 0.009). Fasting glucose, fasting insulin, and homeostasis model assessment-insulin resistance decreased significantly in the DRP group (5.40 ± 0.41 mmol/L vs. 5.21 ± 0.32 mmol/L, P = 0.041; 13.90 [10.50, 18.40] μU/ml vs. 10.75 [8.60, 13.50] μU/ml, P = 0.020; 3.74 [2.85, 4.23] vs. 2.55 [1.92, 3.40], P = 0.008) but did not differ between the two groups. While individual lipid profiles increased in both groups, no statistically significant difference was observed.Conclusions:DRP-containing COCs combined with metformin and lifestyle modifications could better control BP and correct carbohydrate metabolism in women with PCOS and metabolic disorders compared with CPA-containing COCs.Trial Registration:Chinese Clinical Trial Registry, ChiCTR-TRC-11001143; http://www.chictr.org.cn/showproj.aspx?proj=8395.

Background: Use of combined oral contraceptives (COCs) has been found to increase serum 25-hydroxyvitamin D [25(OH)D] but effects on calcium and bone homeostasis are unclear. Materials and Methods: Serum 25(OH)D, parathyroid hormone (PTH), alkaline phosphatase (ALK) and estradiol, dietary intake of bone-related nutrients and foods, bone mineral density (BMD), and body fat were compared in adult women (20-35 years; body mass index 21.5 ± 2.3 kg/m2) users (+COC, n = 32) and nonusers (-COC, n = 20) of COC. Biochemical markers were measured by automated assays. BMD at total body (TB), lumbar spine (LS), femoral neck (FN) and trochanter (TR), and body fat, were measured by dual-energy X-ray absorptiometry. Dietary intake was assessed by a food frequency questionnaire. Results: Intake of calcium, dairy foods, and fruits and vegetables, were adequate and did not differ by COC. Mean 25(OH)D was 35% higher in +COC (110.4 ± 27.3 nmol/L, 44.2 ± 1.8 ng/mL) compared with -COC (81.7 ± 22.8 nmol/L, 32.7 ± 2.3 ng/mL; p < 0.001). Mean PTH, ALK, and estradiol were 28%, 12%, and 62% lower, respectively, in +COC compared with -COC (p ≤ 0.05). Mean BMD z-scores (all sites) were adequate and did not differ by COC. There were no correlations between 25(OH)D and dietary, biochemical, and body composition variables. PTH was inversely correlated with TR-BMD z-score in -COC (r = -0.47; p = 0.04), and ALK was inversely correlated with TB-, TR-, and LS-BMD z-scores in -COC (r ≤ -0.43; p ≤ 0.04), but not in +COC. Conclusions: Increased serum 25(OH)D with COC use was paralleled by expected physiologic adjustments in calcium and bone homeostasis, and adequate bone mass status, in nonobese young adult women consuming bone-healthy diets.

We evaluated the relative contribution of CYP3A in the overall clearance of commonly used combined oral contraceptives (COCs) based on the results of clinical DDI studies in the literature and new drug applications (NDAs). The results revealed a limited role of CYP3A4 in the metabolism of COC components. Characterization of inhibition or induction spectrum of perpetrators on non-CYP3A pathways might also be crucial in predicting drug interaction potential of an investigational new drug with COCs. COC is the most commonly used contraceptive method in the United States.1 Approximately 9.7 million women at reproductive age are COC users.1 COCs usually contain two synthetic steroid hormones, an estrogen, typically ethinyl estradiol (EE), and a progestin. The commonly used progestins include norethindrone (NET), levonorgestrel (LNG), drospirenone (DRSP), norgestimate (NGM), desogestrel, and gestodene.2 Potential drug-drug interactions (DDIs) should be considered when a medication or an herbal supplement is taken with a hormonal contraceptive (HC). The decreased or increased concentrations of estrogen and progestins due to concomitant medications may lead to unintended pregnancy (loss of efficacy) or increased incidence of adverse events (e.g., increased risk of venous thromboembolism, a rare but severe adverse event). Given the high prevalence of COC use in women and possible consequences of unwanted pregnancy, clinical studies to evaluate the DDI potential between an investigational new drug (that is intended to be used in women with childbearing potential) and COCs have been conducted routinely during the drug development stage and sometimes after drug approval. The metabolic pathways of progestins and EE are not completely understood, as many of these steroids were developed >50 years ago with a limited number of studies. The general consensus is that CYP3A is the major enzyme for oxidative metabolism of EE and the commonly used progestins, including NET, LNG, NGM, and DRSP.3-5 Therefore, most DDI studies assessing the effect of other drugs on the exposure of COCs have been conducted based on the possible interaction via CYP3A. However, there is a certain level of variation among progestins in terms of chemical structures, metabolic pathways, and pharmacokinetic (PK) characteristics. In addition, the significance of CYP3A in the overall disposition of these hormones remains unclear. The objective of this study was to assess the relative contribution of CYP3A in the metabolism of steroid hormone components of COCs using publically available clinical DDI study results. The results from the current assessment might give a new insight on the significance of CYP3A-mediated drug interactions with COCs. The results of DDI studies with COCs were collected via (i) literature search using the electronic databases MEDLINE and PubMed from 1996 to November 2014; (ii) publically available US Food and Drug Administration (FDA) review for new drug applications (Drugs@FDA, http://www.accessdata.fda.gov/scripts/cder/daf/) from 1996 to November 2014; and (iii) the University of Washington Metabolism and Transport Drug Interaction Database (http://www.druginteractioninfo.org).6 The following search terms were applied: drug interactions, contraception and oral contraceptives, EE, DRSP, LNG, NET, and NGM. Four progestins (DRSP, NET, LNG, and NGM) containing COCs were selected for this survey, as they are the most commonly used COCs in the United States and are frequently studied in COC DDI studies.2 The following major criteria were applied for the selection of DDI studies for further analyses: (i) prospective clinical studies conducted in healthy subjects or patients to assess a DDI potential with COCs; and (ii) there is sufficient treatment duration of perpetrators for their inhibitory or induction effect on CYP3A (e.g., inhibitors: treatment duration to achieve steady state or shorter duration if it is consistent with clinical use; inducers: longer than 1 week). In addition, to have a relatively clean data set for further analyses, we excluded some DDI studies based on the following criteria: (i) DDI studies that were conducted based on the likelihood of coadministration without a clear mechanism of drug interactions; (ii) case reports; (iii) perpetrators that have mixed CYP3A4 DDI potential (i.e., both inhibition and induction of CYP3A4); (iv) combination drug products containing multiple CYP3A4 perpetrators, which potentially would result in combined DDI effects (i.e., for two-drug combination, inhibition plus inhibition, induction plus induction, and inhibition plus induction); and (v) perpetrators that did not show inhibition or induction effect on sensitive CYP3A substrates in clinical DDI studies. The sample size of the study and its statistical power were not considered for the selection because there were a limited number of studies that provided its rationale based on the power or sensitivity. If there were multiple studies evaluating the same perpetrators, each of them was included in the final analysis to support the conclusion from each other unless it is/they are not representative of clinical scenarios. If differences were found in the DDI study results, causes would be explored. Based on the selection criteria listed above, selected studies were grouped based on the inhibitory and induction potency of perpetrators on CYP3A (i.e., perpetrators are classified as strong, moderate, or weak inhibitors or inducers of CYP3A based on the criteria described in the FDA's draft DDI guidance).7, 8 Specifically, drugs or herbal supplements that increase the area under the curve (AUC) of a sensitive index CYP3A substrate by greater than or equal to fivefold are considered as strong CYP3A inhibitors. Drugs or herbal supplements that increase AUC of a sensitive index CYP3A substrate by twofold to fivefold or less than twofold are classified as moderate and weak CYP3A inhibitors, respectively. Similarly, strong, moderate, and weak CYP3A inducers should decrease AUC of a sensitive index CYP3A substrate by ≥80%, 50–80%, and 20–50%, respectively. The geometric mean ratio (GMR) of AUC for COCs with and without perpetrators are presented using forest plots to illustrate the effect of CYP3A inhibitors and CYP3A inducers on oral contraceptive exposures (Figures 2-5). The plot illustrates the fold-change and 90% confidence intervals (CIs) for AUC of COCs with and without perpetrators observed in the clinical DDI studies. The shaded area shows the GMR between 0.80 and 1.25, the default no-effect boundary, as specified in the DDI guidance. The DDI data for peak concentration (Cmax) are not discussed in the current assessment because the trend of changes in Cmax are, in general, either similar to or lesser than that of AUC for the DDI studies included in the current assessment. In addition, the underlying mechanisms for the changes in Cmax are more complicated to interpret toward the impact on the systemic clearance than that for AUC. In total, 141 clinical drug interaction studies for these four COC products (EE + NET, EE + LNG, EE + NGM, and EE + DRSP) were collected, among which some were conducted with the same perpetrator-COC drug pair. Of these studies, 33 studies were conducted only based on the likelihood of coadministration without any in vitro or in vivo data to specify underlying mechanisms of interaction. Therefore, they were not included in the data analysis. Six studies were excluded for one or more of the following reasons: (i) they were case reports; (ii) they were perpetrators that are thought to have a mixed effect (both induction and inhibition) on enzymes involved in the metabolism of EE and progestins (e.g., aprepitant and ritonavir (inhibitor and inducer of CYP3A))9-12; and (iii) they were DDI studies with combination drug products, such as Stribild (elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate). In addition, 72 studies were excluded from the current review because the perpetrators of these studies had no inhibition or induction effect on sensitive CYP3A substrates, as demonstrated in clinical DDI studies. After reviewing all the studies, 30 studies were selected for further analysis (Figure 1). The magnitude of increase in the exposure (AUC) of EE was not large in the presence of CYP3A inhibitors (Figure 2 and Table 113-26). Strong CYP3A inhibitors, such as voriconazole and ketoconazole, increased EE exposure by 60% and 40%, respectively.13, 14 Telithromycin did not affect the exposure of EE.19 Interestingly, two protease inhibitors, telaprevir and boceprevir, which are known strong CYP3A inhibitors, seemed to decrease the AUC of EE by 26% and 28%, respectively.16, 17 Moderate CYP3A inhibitors, including fluconazole, atazanavir, and faldaprevir, resulted in a 38% to 48% increase in the AUC of EE.20-22, 27 No significant effect on the exposure of EE was observed with other moderate (netupitant23) or weak CYP3A inhibitors.24-26 The effects of CYP3A inhibitors on the systemic exposure of progestins are presented in Figure 3 and Table 1.13-26 Strong CYP3A inhibitors, voriconazole and indinavir, increased the AUC of NET by 53% and 26%, respectively, whereas two strong CYP3A inhibitors, telaprevir and boceprevir, did not significantly affect the exposure of NET.13, 15-17 Coadministration of telithromycin, increased the AUC of LNG by 50%.28 The exposure of DRSP was increased by 100% and 170% when coadministered with boceprevir and ketoconazole, respectively.14, 17, 18, 29 Moderate CYP3A inhibitors showed a modest impact on the exposure of LNG and NET, as demonstrated by <50% increase in the AUCs. Fluconazole, netupitant, and faldaprevir, moderate CYP3A inhibitors, increased the AUC of LNG by ∼25% to up to 40%.21, 23, 27 Unexpectedly, atazanavir, a moderate CYP3A inhibitor, increased the AUC of NET by 110%.22 Weak CYP3A inhibitors seemed to have a negligible effect on the exposure of NET, LNG, and DRSP.24-26 Strong CYP3A inducers, including rifampin, carbamazepine, and phenytoin, reduced the exposure of EE by 38–66% (Figure 4 and Table 230-45). Bosentan and eslicarbazepine, moderate CYP3A inducers, decreased the AUC of EE by 31% and 42%, respectively.30, 31 Efavirenz (a moderate CYP3A inducer) had only 10% reduction in EE exposure, as opposed to a marked effect on progestins, LNG and NGM (Figure 5).32, 33 Oxcarbazepine, which is known as a weak CYP3A inducer, decreased EE exposure by 47%34, 35; nevirapine, a weak inducer, decreased EE exposure by 27%46; perampanel, also a weak inducer, at 4–12 mg daily treatment, did not significantly affect the AUC of EE.36 St John's wort extract, a dietary supplement that exhibited moderate to strong induction on CYP3A4, decreased EE exposure by 14–32%.37, 38 As shown in Figure 5 and Table 2,30-45 strong CYP3A inducers, rifampin and carbamazepine, decreased the AUC of NET by 50–60%.39-41 Carbamazepine and phenytoin decreased the AUC of LNG by 44% and 42%, respectively.42 Moderate CYP3A inducers, efavirenz and eslicarbazepine, decreased LNG exposure by 58% and 37%, respectively.30, 32 Efavirenz also significantly reduced the exposure of norelgestromin (NGMN), a major active metabolite of NGM, by 64%.33 Bosentan, a moderate CYP3A inducer, did not show a significant effect on the exposure of NET.31 The effect of weak CYP3A inducers on progestins varied. Two studies demonstrated that oxcarbazepine significantly decreased the exposure of LNG by 47% and 36%, respectively. Rifabutin and nevirapine showed a small reduction in the AUC of NET (∼10–20%).40, 46, 47 Perampanel demonstrated a dose-dependent effect on the change of the exposure of LNG.48 At the dose of 12 mg per day for 21 days, perampanel decreased the AUC of LNG by 40%, whereas the doses at 8 mg and 4 mg per day had no significant impact on LNG exposure. Lersivirine, another weak CYP3A inducer, slightly decreased the AUC of LNG.43 Two studies demonstrated that St John's wort extract resulted in a 12% reduction on the exposure of NET.37, 38 The current assessments showed that EE and progestins, such as NET and LNG, are minimally sensitive to CYP3A inhibition. The AUC changes of EE and progestins in the presence of a strong CYP3A inhibitor were less than twofold, except for DRSP. Mild inhibitory effect of CYP3A inhibitors on the PK of EE and progestins suggests that CYP3A-mediated oxidation may have limited contribution to the overall disposition of these steroid hormones. EE is extensively metabolized, primarily through intestinal sulfation and hepatic oxidation, glucuronidation and sulfation.3 The oxidative metabolism accounts for the elimination of 30% of EE dose and is catalyzed mainly by CYP3A (67%) and to a minor extent by CYP2C9 (23%).49-51 In addition to CYP-mediated biotransformation, other alternate elimination pathways are glucuronidation by UDP-glucuronosyltransferase 1A1 (UGT1A1) and sulfation by sulfotransferase 1E1 (SULT1E1; Table 35, 14, 17, 29, 49-58). Strong CYP3A inhibitors resulted in no (<1.25-fold) or small increases (<twofold) in EE exposure, suggesting that CYP3A does not contribute significantly to the elimination of EE. Interestingly, two strong CYP3A inhibitors, boceprevir and telaprevir, decreased the exposure of EE. The mechanisms contributing to the decreased exposure of EE remain unclear. The in vitro data indicated that boceprevir and telaprevir have very low or no induction potential for CYP3A.16, 18, 59 Therefore, the reduced EE concentrations are unlikely to be explained by CYP3A induction from boceprevir or telaprevir. The terminal half-life of EE was not changed much when boceprevir was coadministered (14 h and 15 h for EE with and without boceprevir, respectively).17 Based on this observation, it seems that the drug interaction with boceprevir mainly affects the intestine metabolism/efflux (fg) of EE. The EE is a highly permeable drug and its cellular uptake is primarily driven by passive diffusion.3 Although uptake transporters seem to play a minimal role in EE cellular transport, it is possible that EE interacts with efflux transporters, as indicated by the Caco-2 results. In particular, in vitro data showed that EE is a substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein (MRP)-2.3 Boceprevir has been reported as an in vitro P-gp inhibitor with limited in vivo inhibition on digoxin clearance.18 Nonetheless, transporter-mediated drug interactions still cannot explain the findings from the DDI study with boceprevir, as reduced intestine efflux of EE arising from boceprevir-mediated inhibition of P-gp would be anticipated to increase EE exposure, rather than decrease EE exposure. The effect of moderate CYP3A inhibitors on the exposure of EE varied. Interestingly, the effect of atazanavir, a moderate CYP3A inhibitor, as specified by the FDA's draft DDI guidance, on the exposure of EE seemed to be unexpectedly stronger than that of strong CYP3A inhibitors except for voriconazole. It has been reported that the glucuronidation clearance pathway is around 35% of the total clearance of EE and EE 3-O-glucuronidation via UGT1A1 is considered to be the major hepatic UGT pathway.3, 60 Considering atazanavir is known to be a UGT1A1 inhibitor,8, 22 the increase in EE exposure in the presence of atazanavir may be partially due to inhibition of UGT1A1. Metabolic characteristics of progestins have not been well addressed. It was proposed that NET and LNG undergo extensive reduction of α, β-unsaturated ketone of ring A in their steroidal structures forming reduced, and, to a lesser extent, hydroxylated metabolites. The parent drugs and their metabolites can be conjugated, forming sulfated and glucuronidated products, which are excreted primarily in urine, and also in feces5, 61 (Table 35, 14, 17, 29, 49-58). In vitro studies showed that NET is a substrate of CYP3A and the oxidation of NET was inhibited in the presence of ketoconazole, a strong inhibitor of CYP3A.4 Although there is no dedicated study suggesting whether CYP-mediated biotransformation reactions may be of minor relevance compared with reduction and conjugation, the data from current assessment seem to indicate that CYP3A does not play a major role in NET metabolism. In particular, strong CYP3A inhibitors exhibited mild (<50% increase) or no impact on NET exposure. The greatest increase in the exposure of NET was observed (twofold increase) when concomitantly treated with atazanavir, a moderate CYP3A inhibitor. In addition to CYP3A inhibition, atazanavir-mediated inhibitory effect on UGT1A1 may contribute to this interaction.62-64 Thus, observation of more pronounced effects of atazanavir on the systemic exposure of NET may be explained by dual inhibition of CYP3A and UGT1A1. Interestingly, boceprevir and telaprevir also slightly decreased NET exposure, even though they exert a strong inhibitory effect on the metabolism of other CYP3A substrates, such as midazolam. The variable and inconsistent inhibition effect of strong and moderate CYP3A inhibitors on NET may suggest that CYP3A-mediated metabolism is unlikely to be the only major pathway in the clearance of NET and other pathways are likely to also be involved. Mild impact of telithromycin, a strong CYP3A inhibitor, on the exposure of LNG also indicates a limited contribution of CYP3A on the metabolism of LNG. This is consistent with the findings from in vitro studies, in which CYP-medicated biotransformation seemed to be less important compared with reduction and conjugation.65 An in vitro study showed that the biotransformation of DRSP is mainly mediated by reductases, sulfotransferases,29 and CYP 3A contributes only to a minor extent to the metabolism of DRSP (<10%).14, 29 When considering this metabolic fate of DRSP, it is anticipated that an inhibitory effect on CYP3A would have little influence on the exposure of DRSP. However, the multiple dosing of a strong CYP3A inhibitor, ketoconazole, increased the AUC of DRSP by 2.7-fold. The half-life of DRSP was also prolonged when ketoconazole was coadministered.14 Another strong CYP3A inhibitor, boceprevir, increased DRSP exposure by twofold. In vitro data showed that boceprevir is a reversible time-dependent inhibitor of CYP3A, but not an inhibitor of other major CYPs, or of UGT1A1 and UGT2B7.66, 67 In addition, there has been no clinical evidence that ketoconazole or boceprevir inhibit other metabolic enzymes of DRSP, including reductases and sulfotransferases based on our literature search. Therefore, contradictory to the in vitro data, the results of clinical DDI studies with strong CYP3A4 inhibitors ketoconazole and boceprevir indicated the contribution of CYP3A to the metabolism of DRSP. Interestingly, in a similar DDI study design, concomitant dosing of boceprevir showed no impact on NET exposure. Compared with NET and LNG, the significant and consistent increase in the systemic exposure of DRSP by strong CYP3A inhibitors may imply that CYP3A plays a more important role in the metabolism of DRSP than that of NET and LNG. Although the impact of CYP3A inhibition on the metabolism of EE, LNG, and NET is limited, the current survey demonstrated that the exposure of LNG, NET, and EE was significantly influenced by concomitant dosing of CYP3A inducers. In particular, strong CYP3A inducers, such as carbamazepine, rifampin, and phenytoin, and moderate inducer, efavirenz, led to a >50% reduction in the exposure of these COC components. It is noted that these CYP3A inducers have the induction potential of multiple drug metabolizing enzymes, including phase I (CYPs) and phase II (UGT1A1 and SULT1A) enzymes by activating the pregnane X receptor and/or the constitutive androstane receptor.68-74 In addition, nuclear receptors pregnane X receptor and constitutive androstane receptor can mediate the regulation of some aldo-keto reductase, which may play an important role in the biotransformation of NET, LNG, and DRSP.75 Therefore, significant decrease in the exposure of EE and progestins in the presence of these inducers is likely attributed to induction on multiple metabolizing enzymes of steroid hormones including CYP3A, aldo-keto reductase, UGT, and SULT. St John's wort has been known to be a moderate to strong inducer of CYP450 enzymes (particularly CYP3A) and/or transporter proteins, such as P-gp.76 It was reported that consumption of St John's wort may lead to a contraception failure.77 The AUC decrease following pretreatment with St John's wort for both NET and EE in two studies was no more than 32%,37, 38 suggesting a minor change. It is noted that the induction effect of St. John's wort on CYP enzymes varies widely and could be preparation/formulation-dependent.8, 76, 78 The current survey may have several limitations in interpreting the results. The DDI findings were collected from various studies, which had different study designs and treatment dosages of HC and perpetrators. The dose and dosing regimen (single dose vs. multiple doses) of perpetrators may play an important role in determining the magnitude of induction or inhibition effect.48 In addition, some studies included in this survey might have limitations for generalization, such as inadequate sample size and insufficient treatment period. Furthermore, this study did not consider the perpetrators' inhibition or induction potential on drug transporters that may also be involved in the disposition of EE or certain progestins. For example, in vitro data showed that efflux transporters, including P-gp, BCRP, and MRP-2, play a role in EE efflux and EE 3-O-glucuronide (a major metabolite of EE) is a substrate of MRP2 and BCRP.3 However, there have been no dedicated studies examining the impact of these transporters on the overall disposition of EE and progestins. This assessment showed that coadministration of strong and moderate CYP3A inhibitors led to a modest increase in the systemic exposure of EE, LNG, and NET with the exception of DRSP, suggesting that the contribution of CYP3A in the metabolism of EE, NET, and LNG is not predominant. DRSP seemed to be more sensitive to CYP3A inhibition compared with NET and LNG. In contrast, strong CYP3A inducers seemed to impose a marked reduction in the systemic exposure of EE, LNG, NET, and NGM (>40% decrease). It may be explained by the possibility that CYP3A inducers used for those studies had induction potential of multiple drug metabolizing enzymes including phase II (UGT1A1 and SULT 1A) in addition to phase I (CYPs) enzymes and/or transporters involved in the disposition of EE and progestins. Characteristics of inhibition or induction spectrum of perpetrators on non-CYP metabolic pathways (e.g., glucuronidation and sulfation) and/or transporters should be considered in predicting and interpreting the overall DDI potential with COCs. As observed from this survey, the same perpetrator had different effects on different progestins (in combination with EE), which pose a challenge in extrapolating the study findings of one specific progestin containing hormonal contraception to the other products. The results may also shed a light on the selection of progestins for DDI assessment based on perpetrators' characteristics. More research is needed to understand the metabolic and transporter pathways of EE and progestins as well as relative contribution of each pathway in their clearance. Such information could enable us to utilize physiologically based PK modelling to predict the DDI potential with various HCs and routes of administration.8 The authors thank Na Hyung Kim and Su-Young Choi for their prior contributions to the current research. This research was supported by the US Food and Drug Administration's (FDA's) Office of Women's Health. Dr Nan Zhang was supported by an appointment to the Research Participation Program at the Center for Drug Evaluation and Research, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the FDA. Part of the study was presented at 2015 ASCPT Annual Meeting. The authors declared no conflict of interest. The views described are those of the authors and do not necessarily represent the position of the US Food and Drug Administration or the US government.

Appropriate follow up to detect potential adverse events after initiation of select contraceptive methods: a systematic review

Combined oral contraceptives (COCs) are now widely used. There are some doubts regarding adverse events while taking COCs due to conflicting research data, which requires detailed clarification of all risks and the incidence of adverse events. One of the most common complaints of patients taking COCs is the occurence of unaesthetic varicose veins of the lower extremities. However, no data to support this have been found in the literature. The authors describe the reversible effect of COCs on the venous wall tone and the formation of hormone-induced phlebopathy, which is safely stopped by original phlebotonics. Potentially significant adverse vascular events associated with the use of COCs include venous thromboembolic complications, which are directly proportional to the duration of drug administration and its composition. It is also noted that the use of COCs has no significant effect on the hemostatic system, which has some limitations in terms of laboratory control. Conclusion. СOCs have some effect on the venous wall, but the progression of chronic venous disorders tends to have another source. There are risks of thrombosis, but significantly lower than certain physiological conditions in women. Key words: hemostasis, adverse events, oral contraceptives, thrombosis, phlebopathy

Impact of estrogen type on cardiovascular safety of combined oral contraceptives

Premenstrual syndrome (PMS) is a common problem. Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual syndrome. Combined oral contraceptives (COC), which provide both progestin and oestrogen, have been examined for their ability to relieve premenstrual symptoms. A combined oral contraceptive containing drospirenone and a low oestrogen dose has been approved for treating PMDD in women who choose combined oral contraceptives for contraception. To evaluate the effectiveness and safety of COCs containing drospirenone in women with PMS. We searched the Cochrane Gynaecology and Fertility Group trial register, CENTRAL (now containing output from two trials registers and CINAHL), MEDLINE, Embase, PsycINFO, LILACS, Google Scholar, and Epistemonikos on 29 June 2022. We checked included studies' reference lists and contacted study authors and experts in the field to identify additional studies. We included randomised controlled trials (RCT) that compared COCs containing drospirenone with placebo or with another COC for treatment of women with PMS. We used standard methodological procedures recommended by Cochrane. The primary review outcomes were effects on premenstrual symptoms that were prospectively recorded, and withdrawal due to adverse events. Secondary outcomes included effects on mood, adverse events, and response rate to study medications. We included five RCTs (858 women analysed, most diagnosed with PMDD). The evidence was very low to moderate quality; the main limitations were serious risk of bias due to poor reporting of study methods, and serious inconsistency and imprecision. COCs containing drospirenone and ethinylestradiol (EE) versus placebo COCs containing drospirenone and EE may improve overall premenstrual symptoms (standardised mean difference (SMD) -0.41, 95% confidence interval (CI) -0.59 to -0.24; 2 RCTs, N = 514; I2 = 64%; low-quality evidence); and functional impairment due to premenstrual symptoms in terms of productivity (mean difference (MD) -0.31, 95% CI -0.55 to -0.08; 2 RCTs, N = 432; I2 = 47%; low-quality evidence), social activities (MD -0.29, 95% CI -0.54 to -0.04; 2 RCTs, N = 432; I2 = 53%; low-quality evidence), and relationships (MD -0.30, 95% CI -0.54 to -0.06; 2 RCTs, N = 432; I2 = 45%; low-quality evidence). The effects from COCs containing drospirenone may be small to moderate. COCs containing drospirenone and EE may increase withdrawal from trials due to adverse effects (odds ratio (OR) 3.41, 95% CI 2.01 to 5.78; 4 RCT, N = 776; I2 = 0%; low-quality evidence). This suggests that if you assume the risk of withdrawal due to adverse effects from placebo is 3%, the risk from drospirenone plus EE will be between 6% and 16%. We are uncertain of the effect of drospirenone plus EE on premenstrual mood symptoms, when measured by validated tools that were not developed to assess premenstrual symptoms. COCs containing drospirenone may lead to more adverse effects in total (OR 2.31, 95% CI 1.71 to 3.11; 3 RCT, N = 739; I2 = 0%; low-quality evidence). This suggests that if you assume the risk of having adverse effects from placebo is 28%, the risk from drospirenone plus EE will be between 40% and 54%. It probably leads to more breast pain, and may lead to more nausea, intermenstrual bleeding, and menstrual disorder. Its effect on nervousness, headache, asthenia, and pain is uncertain. There was no report of any rare but serious adverse effects, such as venous thromboembolism in any of the included studies. COCs containing drospirenone may improve response rate (OR 1.65, 95% CI 1.13 to 2.40; 1 RCT, N = 449; I2 not applicable; low-quality evidence). This suggests that if you assume the response rate from placebo is 36%, the risk from drospirenone plus EE will be between 39% and 58%. We did not identify any studies that compared COCs containing drospirenone with other COCs. COCs containing drospirenone and EE may improve premenstrual symptoms that result in functional impairments in women with PMDD. The placebo also had a significant effect. COCs containing drospirenone and EE may lead to more adverse effects compared to placebo. We do not know whether it works after three cycles, helps women with less severe symptoms, or is better than other combined oral contraceptives that contain a different progestogen.

It is important to choose a combined oral contraceptive (COC) after an abortion operation, since the requirements for a contraceptive prescribed during this period have their own specifics. It is necessary to stop as many negative consequences for the woman's body caused by the termination of pregnancy and, in addition, to ensure maximum safety of the prescribed drug. The relevance of this topic is due to the need to choose the safest and most effective contraceptive. A study was conducted of the effect of monophasic low-dose COCs, which is a combination of 0.15 mg levonorgestrel and 0.03 mg eeinylestradiol 0.03 mg in each tablet (PlaniGenslevo) on the state of the body and endothelial function in 22 women of reproductive age using the drug for 3 months after an artificial abortion and belonging to the first category of acceptability of COCs. As a control, the results of a test with reactive hyperemia were evaluated in 22 healthy women aged 19 to 35 years. As a result of the study, there was no increase in body mass index, blood pressure, changes in metabolic parameters in the biochemical analysis of blood, as well as an increase in the duration of menstrual bleeding, the absence of intermenstrual bleeding, as well as breast swelling, headaches, dyspeptic phenomena and other adverse events that may be caused by taking COCs in women using Women's Left within 3 months. The conducted study demonstrated the absence of adverse events on the part of the body of women taking after abortion Plani Women left. In addition, there were no statistically significant changes compared to the control group in the results of the test with reactive hyperemia, reflecting the absence of endothelial dysfunction in women using the contraceptive Plani Women left, which can serve as confirmation of the absence of a negative effect of the drug on the cardiovascular system.

Asians have different body fat distributions and disease characteristics compared with Caucasians. The purpose of this study was to evaluate general and central obesity, combined oral contraceptive (COC) use, and their joint effects on the risk of hypertension in Chinese women. A case-control study including 1,760 women (878 hypertensive cases and 882 normotensive controls) was conducted in China. Body weight, height, waist circumference (WC), blood pressure, serum lipids, and apolipoproteins were measured. History of contraceptive use and relevant factors were investigated. Odds ratio (OR) with 95% confidence interval (CI) was estimated for hypertension-related factors under unconditional logistic regression model. Our study showed that increased body mass index (BMI), increased WC, and COC use were risk factors for hypertension with an OR (95% CI) of 2.19 (1.69-2.83), 1.46 (1.13-1.88), and 1.26 (1.02-1.56), respectively. Compared with WC, BMI was more strongly associated with hypertension risk (OR 3.40, 95% CI 2.28-5.05, for highest vs. lowest quartile) and was a better predictor for blood pressure. COC users had a 1.39-fold (OR 1.39, 95% CI 1.14-1.69) increased risk compared with the nonusers, while stopping COC was associated with a 36% reduced risk (OR 0.64, 95% CI 0.42-0.98). The risk increased dramatically in combination of COC use with a BMI ≥28 kg/m(2) or WC ≥90 cm (OR 8.02, 95% CI 5.05-12.74; OR 5.76, 95% CI 3.65-9.12, respectively). General and central obesity, COC use, and their joint effects significantly increased the risk of hypertension in Chinese women.