European Review for Medical and Pharmacological Sciences 2020; 24: 11810-11819 Safety, efficacy and quality of life of the novel vaginal contraceptive ring containing etonogestrel/ethinylestradiol 11.0/3.474 mg after 3 years of “real life” experience

A. MÜLLER1, M. SAILER1, E. COLLI3, P.-A. REGIDOR3

1Exeltis Germany GmbH, Ismaning, Germany 2Exeltis HealthCare Madrid, Madrid, Spain 3Exeltis Europe, Ismaning, Germany

Abstract. – Combined contraceptive vaginal by the woman herself. VR of different polymer rings (CVR) are increasingly appreciated due to composition and therapeutic purposes have been several beneficial properties like avoidance of developed, including estrogen-releasing VRs for the hepatic first-pass effect, a comparatively management of menopausal symptoms2,3 or VRs low dosage of hormones and comfortable use. for the treatment of deep pelvic endometriosis4 A further development of the widely used CVR 5 releasing 0.12 mg etonogestrel (ETO) and 0.015 or long-term delivery of a HIV microbiocide . mg ethinylestradiol (EE) per 24 hours has been They have gained immense importance in the marketed since 2017. The 11.00/3.474 mg ETO/ field of hormonal contraception, as they offer EE CVR Ornibel® is bioequivalent to the former several advantages compared to their oral, intra- product but differs in its polymer composition uterine or transdermal counterparts. They do not leading to improved stability. require daily application like oral contraceptives Here, results from recent studies on the nov- el CVR Ornibel® are reviewed including clinical (OC), are nonetheless patient-controlled and their trials on bleeding profile, acceptability, sexual constant hormonal release rate results in low- function and other quality of life (QoL) parame- er systemic hormone exposure compared to OC ters as well as in vitro studies on microbial ad- or transdermal patches6. Consequently, vaginal hesion to the CVR and the influence of ring rup- contraceptive rings have become increasingly im- ture on hormone release. Findings are comple- portant in both higher and lower income countries mented with new data on contraceptive efficacy and are generally well accepted by the women, and safety of the new CVR that were assessed 7,8 during 3 years of real-life experience. when adequate counselling is provided . Dif- ferent variants of progestin-only rings have been Key Words: developed for contraception but were associated Vaginal contraceptive ring, Elution, Safety, Efficacy. with unfavorable bleeding patterns and did not suppress ovulation9. Consequently, development progressed towards combined contraceptive vag- Introduction inal rings and different combinations of estradiol or ethinylestradiol and progestin were studied10-14. The vaginal route of drug administration of- Nowadays the CVR combining ethinylestradiol fers several advantages compared to oral dosage (EE) and etonogestrel (ETO) has prevailed due forms. It is not impaired by gastrointestinal dis- to its excellent contraceptive efficacy, favorable turbances or interferences with additional oral safety profile, advantageous cycle control and medication. Furthermore, the hepatic first pass high user acceptability11,15. NuvaRing®, market- effect is avoided, which allows for lower drug ed since 2001, is a transparent, ring-shaped de- dosing and may generally result in fewer side ef- vice measuring 54 nm in diameter and 4 mm in fects1. Hence, the development of vaginal rings cross-section and consists of a core made from (VR) in women’s health has started in the 1960s, magnesium stearate plus 28% ethylene vinylac- offering a drug-delivery platform for continuous etate (EVA) and is covered by an external mem- release of therapeutics that can easily be applied brane containing 9% EVA. Loaded with 11.7 mg

11810 Corresponding Author: Pedro-Antonio Regidor, MD; e-mail: [email protected] Etonogestrel/ethinylestradiol 11.0/3.474 mg vaginal contraceptive ring

ETO and 2.7 mg EE, it releases on average 0.120 EE), but the average daily release and resulting mg ETO and 0.015 mg EE within 24 h when in- plasma concentrations were proven bioequiva- serted into the vagina15. The ring is usually placed lent19. In this randomized crossover comparative into the vagina at day 1 of the cycle and is re- bioavailability study, the ETO- and EE plasma moved after 3 weeks of use. During the following concentrations of women using Ornibel® were ring-free interval of 1 week, withdrawal bleeding compared to those of NuvaRing® users, during occurs and finally, a new ring is inserted. Follow- an application period of 28 days. Bioequivalence ing this regimen, ovulation is suppressed and con- was demonstrated as the primary parameters lay traceptive efficacy comparable to that of oral con- within the requested 80-125% acceptance range traceptives (OC) is maintained from the first day for both ETO and EE (Figure 1)19. However, a dif- of use and throughout the ring-free interval15-17. In ference in drug delivery during the first day of use contrast to OC however, the hormones are provid- was observed with NuvaRing® showing a signifi- ed more uniformly and in lower concentrations, cant peak release of the active compounds (“burst which may reduce EE-induced side effects18. effect”, Figure 1). The phenomenon is especially noticeable for EE and leads to peak concentra- An ETO/EE CVR of Novel Polymer tions that are higher than the mean level for the Composition: Hormone Release, next few days and were also significantly high- Pharmacokinetics, and Stability er than those observed for the novel CVR. The In 2017, a novel ETO/EE CCVR with the same burst effect is a known phenomenon for NuvaR- size and external appearance as NuvaRing® was ing®20 and has been associated with nausea and approved for market. Ornibel® (developed by Lab- vomiting in a further CVR containing norethin- oratories LeonFarma, SA, Chemo Group, León, drone and ethinyl estradiol21. The more gradual Spain) contains the same active compounds as the hormone release from the novel ETO/EE CVR is reference product NuvaRing® and its bioequiva- attributed to the different polymer composition, lence was demonstrated19. Albeit approved as a which allows dissolution of the hormones below generic drug, it differs in its polymer composition their saturation limit resulting in higher stability with its core consisting of polyurethane and an of the system. This also leads to the benefit that no outer membrane containing 28% EVA. This alter- cold chain is needed when handling the device22 ation allows the hormones to be dissolved below thus manifesting an advantage for pharmacists the saturation limit as opposed to the reference and users. This comparative study also showed product. Slightly different amounts of active com- the high acceptability of Ornibel® among the us- pounds are loaded (11.0 mg ETO and 3.474 mg ers, equal local tolerability and an advantageous

Figure 1. Mean plasma concentration-time curves of etonogestrel (squares) and ethinylestradiol (circles) by treatment with the novel CVR (black) or its reference product (gray) during four weeks of use and 1 week after removal.

11811 A. Müller, M. Sailer, E. Colli, P.-A. Regidor risk profile as determined from adverse events19. Bleeding Pattern, Acceptance, Sexual Concerning hormone release, the elution of Function, And Quality Of Life with the ETO and EE from broken Ornibel® vaginal rings Novel CCR in comparison to intact ones was investigated in Many different parameters influence women’s vitro23. CVRs occasionally break during use17,22, decision for and adherence to a contraceptive which frequently raises the question, whether the method. For example, ease of use in daily life, clinical efficacy is maintained in these cases. For probability of omission, adequate cycle control, a that purpose, a fully validated in vitro elution favorable side effect profile and further non-con- method (IVE) was applied which has also been traceptive benefits26. For Ornibel®, a retrospective used for the regulatory procedures during market multi-center observational study with 103 wom- authorization of the novel vaginal ring. Contra- en, wo used the novel CVR for at least 6 months ceptive rings from the same batch were either was performed to assess its impact on bleeding cut or left intact and were incubated in a defined profile, dysmenorrhea, general acceptance and elution buffer for 21 days. Daily hormone elution the continuation rate27. After 6 months of appli- was determined by HPLC. For both ETO and EE cation, unscheduled bleeding or spotting was the hormone release was similar for intact and reduced from 21% to 12% and furthermore, a broken rings and were within the acceptance lim- significant reduction of menstrual flow and dys- its specified for the device. Resulting elution pro- menorrhea was observed as determined by a VAS files for ETO and EE are shown in Figure 2 and scoring system. As displayed in Figure 3, median demonstrate the equivalence of hormone release reduction was 16 points (p<0.002) for menstrual between broken and intact Ornibel® VR. The IVE flow and 22.5 points (p<0.001) for dysmenorrhea. test system allows some extrapolations to the situ- Hence, as described for NuvaRing®28, the novel ation in vivo, since it is based on an in vivo/in vitro CVR shows beneficial effects on cycle stability correlation model of category A as defined by the and bleeding parameters. Evaluation of additional FDA 24 and can potentially be used for bioequiv- aspects associated with quality of life (Qol) re- alence studies25. Therefore, it may be concluded vealed that the vast majority (97%) of users rated that a rupture of the ring will not influence the the ring as very comfortable or comfortable and pharmacokinetic behavior of released ETO and agreed that it was easy to insert (91%). These per- EE and will not impair the overall efficacy and ceptions were significantly associated with the safety of CVR16,11. willingness to continue usage of the contraceptive

Figure 2. In vitro elution of ETO (squares) and EE (circles) from intact (gray) and broken (black) Ornibel® vaginal rings. Each 6 rings were broken at day 1 or left intact and were incubated in the IVE buffer system for 21 days. Mean daily release of the hormones (µg/day) is displayed (error bars: standard deviations between replicates).

11812 Etonogestrel/ethinylestradiol 11.0/3.474 mg vaginal contraceptive ring

Figure 3. A, Median VAS score values for menstrual bleeding before (blue) and after (red) the 6-months treatment with Ornibel®. 75th, 50th and 25th percentiles are given. Median reduction of 16 points (p<0.001). B, Median VAS Score values for dysmenorrhea before (blue) and after (red) the 6-months treatment with Ornibel®. 75th, 50th and 25th percentile. Median reduction of 22.5 points (p<0.001). Adapted from reference 27. method (91%) and to recommend it to other wom- more pronounced in the group utilizing the novel en (95%). Only 15% of the participants mentioned device. Improvement in PMS and dysmenorrhea occasional interference with daily activities and were observed in both groups and did not differ usually (in 88% of cases) the partners did not or significantly between the CVRs. Furthermore, the only occasionally notice the ring during sexual breakthrough bleeding rate was slightly higher in intercourse27. The superior cycle control of CVRs the NuvaRing® group causing discontinuation of compared to COCs due to the constant low-dose the contraceptive method in 13.8% of the cases31. release of EE has been demonstrated in several The authors speculated, whether the reduced burst clinical studies and is characterized by low rates effect with the novel CVR might be accountable of irregular bleeding among VR users28-30. Also, for the observed differences. However, since no the general good acceptability and high contin- plasma hormone levels had been determined, no uation rates have been shown for the ETO/EE direct conclusions could be drawn. Furthermore, CVR16,28,29. Both aspects have been observed for the number of participants in the trial had been low. the novel CVR19,27. Nevertheless, the study confirmed the high accept- A further randomized comparative study as- ability and beneficial effects of the novel CVR, in- sessed the influence of Ornibel® on female sexual cluding its positive impact on sexual function. function and Qol compared to women using Nu- vaRing®31. 58 women who did not use hormonal Microbial Adhesion to Ornibel® contraception were randomly assigned to two Compared to NuvaRing® groups and either started using Ornibel® or the Although combined contraceptives rather seem reference product. After 3 and 6 months FSFI (fe- to positively influence the vaginal flora32 or even male sexual function index), FSDS (female sexu- exert a positive or stabilizing effect33 also in the al distress scale), Qol parameters (determined by case of VRs34, higher incidences of vaginal infec- SF-36 questionnaire), occurrence of premenstrual tions and irritations with CVR users compared syndrome (PMS) and dysmenorrhea (each as- to women using COC28,29 have been reported for sessed via VAS scoring) were compared. In both contraceptive vaginal rings and according to the groups, FSFI, FSDS and Qol parameters improved SPCs, vaginal infections are frequently reported after 6 months, but improvement was faster and (incidence 1/100-1/10)17,22.

11813 A. Müller, M. Sailer, E. Colli, P.-A. Regidor

One of the major pathogens causing vaginal a possible causal relationship to the use of a me- infections is the human commensal Candida al- dicinal product. All kinds of reporting resourc- bicans, which colonizes the vaginal tract and may es must be considered (including for example turn into a pathogen under certain circumstanc- healthcare providers, consumers or reports in the es35. Its ability to adhere to medical devices with literature), evaluated and classified according to subsequent biofilm formation is an important Eudra guidelines41 and resulting individual case virulence factor in this context36. A recent in-vi- safety reports (ICSR) are provided to central reg- tro study analyzed the adhesion of C.albicans to ulatory authorities. Unintended pregnancies are Ornibel® in comparison to NuvaRing® and was also covered by this system and we used this data found significantly lower of for the novel device37. to roughly estimate the number of contraceptive In contrast, no difference in adhesion was ob- failures per 100 woman-years of exposure (Pearl served for Lactobacillus acidophilus. When the Index, PI). Until end of June 2020 13 pregnancies CVRs were co-incubated with both types of mi- (confirmed or potential pregnancies) were report- croorganism, no difference in colonization were ed, while 2573018 cycles have been sold to the observed for C.albicans, but significantly lower customers (“sell-out data”). From this data, the PI numbers of L.acidophilus CFUs (cell forming was estimated as follows: units) were counted on Ornibel® compared to Nu- vaRing®. Interestingly, previous scholars38 have (100* number of pregnancies*13) shown, that presence of lactobacteria enhances PI = ––––––––––––––––––––––––––––––– the adhesion capacity of C.albicans to a CVR (number of cycles) in vitro. It may thus be speculated, whether a re- duced number of lactobacilli on Ornibel® might Assuming all sold cycles have been used, this lead to reduced virulence of C.albicans in vivo. resulted in an extremely low PI of 0.007. The ca- However, interactions between microorganisms, pacity of ETO/EE CCVR to efficiently suppress- vaginal epithelium and medical devices are high- ing ovarian function and inhibiting ovulation reli- ly complex in vivo and further extended studies ably even in certain scenarios of non-intended use will be necessary to understand the practical rele- has been described for NuvaRing®42. According to vance of the observation. the specifications, PI ranges between 0.64-0.9617,22 Differences in surface roughness between the and is considered comparable to COCs with PIs devices might be a reason for altered microbial ad- ranging between 0.29 and 1.98 depending on dos- hesion but could not be confirmed by comparative age, composition, and further parameters43. For scanning electron microscope (SEM) analyses39. both CVR and COC the WHO describes the PI for However, these SEM studies were performed on consistent and correct use with 0.3, rising to 7 for “fresh” CVRs and surface conditions might be common use44. In Figure 4 the estimated PI of the different after incubation of the ring in buffer novel CRV is compared to that of several hormon- systems (or the vaginal environment). Hence, the al contraceptive methods as given by the WHO topic needs further investigation. for correct use. The evaluated pharmacovigilance data for Ornibel® may be biased, since not every Contraceptive Efficacy of Ornibel® single sold VR may have been utilized and not Contraceptive efficacy is a key feature for con- every unintended pregnancy may have been re- traception. For the novel CVR, no unintended ported. Nevertheless, it speaks for the high con- pregnancies have been reported during the clini- traceptive efficacy of the novel CVR. cal trials19,27,31. These trials had not been intended to evaluate contraceptive efficacy and included a Safety of Ornibel® limited number of participants. Hence, in order The safety of the novel CVR® regarding adverse to obtain further data from “real life”, reporting events was proven in several clinical studies19,27,31 of unintended pregnancies by the established showing a general advantageous risk profile and German pharmacovigilance surveillance system similar incidences of adverse events as the refer- were evaluated. According to German pharma- ence product. Furthermore, the safety of the new ceutical law and the EMA guidelines on good CVR was assessed based on pharmacovigilance pharmacovigilance practice (GVP)40, each mar- reporting of serious adverse events (SAE) accord- keting authorization holder is obliged to provide ing to Eudra Classification41. Until the end of July a pharmacovigilance system that ensures proper 2020, 10 SAE were reported for the novel CVR, collection of reports on all adverse reactions with including 4 cases of venous thromboemholism

11814 Etonogestrel/ethinylestradiol 11.0/3.474 mg vaginal contraceptive ring

The risk for thrombotic stroke or myocardial in- fection was reported to be comparable to that of EE/LNG COCs56. For Ornibel®, no aortic thromboembolism (ATE) and 4 cases of VTE were reported since its launch in 2017, including the clinical trials. Obviously, only a rough estimation for VTE in- cidence can be made, since our data is not based on a clinical trial but on pharmacovigilance data. Hence, there is no information available on the user population. We can also not rule out that VTE may have been missed. Based on 2335955 cycles sold to the customers and assuming 13 cy- cles per woman, such a rough estimation would Figure 4. Contraceptive effectiveness of different hormonal contraceptive methods compared to the novel CRV. PI data result in 0.2 VTE per 10000 woman-years, which for consistent and correct use of the respective contraceptive is far below the values cited above: methods as given by WHO42 are displayed and compared to Data obtained for the new ETO/EE CVR® after 3 years of (10000* number of VTE*13) marketing. PO-inj: Progestin-only injectable; Patch: com- Incidence of VTE = ––––––––––––––––––––––––––––– bined contraceptive patch; COC: combined oral contracep- tive; POP: progestin-only pill; CVR: combined vaginal ring; (number of cycles) Levo-IUD: intrauterine device releasing levonorgestrel. In Figure 5 the estimated VTE incidence for use of the novel CRV is compared to the estima- (VTE) (1 case of deep vein thrombosis, 1 case of tions given for the above-mentioned methods of 1 sinus vein thrombosis and one case of pulmo- hormonal contraception visualizing the compara- nary embolism), Urticaria (1 case), Angioedema tively low rate of venous thromboembolic events. (1 case), Cervical eversion (1 case), a general state The superiority of non-oral delivery of Estrogen of fatigue associated with depression and consti- concerning hemostatic safety has been discussed pation (1 case), exacerbation of Morbus Crohn (1 and was shown for 17beta-estradiol57. However, case) and 1 case of emotional stress due to broken the potency of vaginal EE to stimulate alterations ring . in hemostatic variables and estrogen-sensitive Generally, the use of COCs containing EE is liver proteins was shown to be comparable to the associated with an in increased risk of VTE com- effects of oral administration despite avoidance pared to non-users, although the absolute risk of the hepatic first pass effect58. Our observations remains low and is significantly raised among nevertheless indicate a high thromboembolic pregnant women and post-partum45. While for safety of the novel CVR. Whether the described non-users the absolute risk for VTE is estimat- reduction of the burst effect might have an influ- ed to be about 2 per 10000 women per year for ence on these parameters is worth further inves- non-pregnant women, it increases 2-4-fold for tigation. COCs depending on the estrogen dose and kind of progestin used46. It is also highly dependent on Implications for Current Challenges additional risk factors, such as overweight and a Regarding COVID-19-Disease family history of thrombosis and differs between In SARS COVID-19 pandemic times the safety studies45,47. At present oral combinations with le- aspects of these vaginal rings will get more and vonorgestrel, norethisterone or norgestimate (2nd more important. SARS-CoV-2 appears to prefer- generation) are considered to impose the lowest entially target respiratory epithelium, where it en- risk with an estimated incidence of 5-6 VTE per ters host cells through the angiotensin-converting 10000 women and year and are considered first enzyme 2 (ACE2) receptor, like SARS-CoV59,60. choice in current guidelines48,49. However, all infectious complications in critical- For non-oral combined contraception, an ele- ly ill patients are known to activate multiple sys- vated VTE risk compared to non-users is also as- temic coagulation and inflammatory responses sumed50,51. Concerning the CVR, it is considered that are vital for host defense and can lead to a comparable to that of EE/LNG COCs51-54 and in disseminated intravasal coagulopathy (=DIC)61,62. one cohort study55 a modest increase was shown. Microorganisms and their components induce

11815 A. Müller, M. Sailer, E. Colli, P.-A. Regidor

Figure 5. Estimated VTE risk of the novel ETO/EE CVR in comparison to VTE risks of different hormonal contraceptives (HC) compared to non-pregnant non-users of hormonal contraception47-49. HC: hormonal contraceptive; POP: progestin-only pill; EE: Ethinylestradiol; Levo: Levonorgestrel; Norg: Norgestimat; Norelg: Norelgestromin; DNG: Dienogest. the expression of numerous products, including agulation is the probable cause for the elevated tissue factor by binding to pattern-recognizing levels of D-dimers. Such an increase can result receptors on immune cells63-65. The triggering of from many conditions other than thromboembo- host inflammatory reactions also results in in- lism, with infection being an important cause70. To creased production of proinflammatory cytokines minimize additional cardiovascular risk factors is that have pleiotropic effects, including activation therefore essential in COVID-19 times. Hence, all of coagulation which, if not checked, can lead to contraceptive systems free of oestrogens like POP consumptive coagulopathy. with desogestrel or drospirenone can be considered Coagulation is activated by the inflammatory as safe as they do not activate the coagulatory axis response through several procoagulant pathways. in the liver. Concerning combined contraceptives, Polyphosphates, derived from microorganisms, the estrogen dose should be kept as low as possible, activate platelets, mast cells, and factor XII (FXII) which is ensured by vaginal delivery systems like in the contact pathway of coagulation, and exhibit Ornibel®. further downstream roles in amplifying the pro- coagulant response of the intrinsic coagulation pathway66. Complement pathways also contribute Conclusions to the activation of coagulation factors67. Although neutrophil extracellular traps are present in throm- Vaginal contraceptive rings with their high bi, the individual neutrophil extracellular trap com- contraceptive efficacy, ease of use, and beneficial ponents of cell-free DNA and histones activate the safety profile represent an essential option in the contact pathway and enhance further prothrom- field of hormonal contraception7. The combined botic pathways resulting in thrombin generation8,18. 0.120/0.015 mg ETO/EE 24 h vaginal hormone Pathogen-associated molecular mechanisms are delivery system has been established since 2001, important aspects of the complex interactions be- but required a cold chain17 and showed a signifi- tween the immune response and coagulation as cant hormone peak release during the first day of well as in sepsis63,68. The inflammatory effects of use19,20. These drawbacks were overcome by the cytokines also result in activated vascular endothe- development of the novel CVR with improved lial cells and endothelial injury with resultant pro- thermodynamic stability due to a different poly- thrombotic properties63,69. mer composition19,22. The bioequivalence of the The inflammation processes associated with device and its high tolerability, safety, and effi- COVID-19 and the subsequent activation of co- cacy were proven in clinical studies19,27,31, and the

11816 Etonogestrel/ethinylestradiol 11.0/3.474 mg vaginal contraceptive ring hormone release was found unaltered in ruptured among women in low- and middle-income coun- rings23, adding a further aspect of safety. With tries: a systematic review and narrative synthesis. very low incidences of SAE, including VTEs and PLoS One 2019; 14: e0224898. unintended pregnancies during three years of 9) Ahrén T, Victor A, Lithell H, Vessby B, Jackanicz TM, Johansson ED. Ovarian function, bleeding control “real-life experience” the new VCR constitutes and serum lipoproteins in women using contra- a valuable advancement in the field of hormonal ceptive vaginal rings releasing five different pro- contraception. Its beneficial safety aspects may gestins. 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