NuvaRing: eerste ervaringen in Nederland Dr. Frans Roumen Atrium Medisch Centrum Heerlen 17-10-2003

Ontwikkeling van hormonale anticonceptiva Verlaging van hormoon dosering Meer selectieve progestagenen Alternatieve methoden van toediening Hormonal contraceptive development has focused on reducing hormone doses, developing more selective progestogens, and investigating alternative routes for administration. The current generation of contraceptives contains a substantially lower dosage of ethinylestradiol than the first licensed products. This reduction has minimized the occurrence of estrogen-associated adverse events, such as thrombotic complications, changes in the hemostatic system, and less serious but still troublesome side effects like nausea, headache, vomiting and breast tenderness. Progestogen dosages have also been reduced, and more selective progestogens developed. Increased selectivity is characterized by high progestogenic activity, and low affinity for the androgen receptor. Consequently, contraceptives containing these progestogens are less likely to produce adverse androgenic events, such as changes in lipid metabolism, glucose intolerance and acne and hirsutism. Alongside the optimization of contraceptive hormones, alternative methods of administration have been investigated; non-oral routes of drug delivery avoid some of the disadvantages of oral delivery, and offer women a wider choice of contraceptive methods with enhanced convenience.

Voordelen van niet-orale toedieningsvormen Dagelijkse pilinname niet nodig Geen gastro-intestinale interacties Geen hepatisch first-pass effect Mogelijkheid om gebruik te maken van “controlled-release” preparaten ter verkrijging van constante serum concentraties Verdere verlaging van doseringen Alternative routes for the administration of contraceptive hormones have been investigated, primarily to avoid some of the disadvantages associated with oral drug delivery, but also to add more convenient methods to the current choice of contraceptives. Delivering contraceptive hormones via non-oral routes avoids gastrointestinal interference with absorption and hepatic first-pass metabolism. In addition, several non-oral administration routes allow the use of controlled-release formulations; these formulations have the advantage of delivering hormones at a uniform rate, achieving (almost) constant serum concentrations. All these properties provide the opportunity to reduce hormone dosages compared with oral formulations. Next to these clinical benefits, the most appealing benefit to the user would be the avoidance of daily pill intake.

de vaginale route “De toediening van medicijnen via de vagina is vooral geschikt voor geneesmiddelen op het gebied van typisch vrouwelijke gezondheidskwesties” (Woolfson AD et al, 2000)

Additionele voordelen vaginale toediening Langere termijn vorm van anticonceptie (maandelijkse methode; tenminste 3 weken) Eenvoudige plaatsing en verwijdering door de gebruikster zelf Constante en zeer lage hormoonafgifte Discreet The vagina as a route for drug delivery is an established concept. The concept of using a vaginal ring for the delivery of contraceptive hormones was first described in 1970. Using a vaginal ring as a contraceptive has several potential advantages. The method is easy to insert and remove by the woman herself; avoiding the need for intervention by a physician and giving the woman more control over her own method. It avoids the need for daily pill intake, it achieves constant serum hormone concentrations, maintains a cyclic and thus predictable pattern of bleeding, and allows a rapid return to ovulation after stopping ring use. The clinical development of vaginal rings was therefore started on the basis that vaginal rings could be an effective and convenient method for the delivery of contraceptive hormones. (Once a month, ease of use, control leading to freedom)

Nadeel vaginale toediening Drempelvrees eerste keer The vagina as a route for drug delivery is an established concept. The concept of using a vaginal ring for the delivery of contraceptive hormones was first described in 1970. Using a vaginal ring as a contraceptive has several potential advantages. The method is easy to insert and remove by the woman herself; avoiding the need for intervention by a physician and giving the woman more control over her own method. It avoids the need for daily pill intake, it achieves constant serum hormone concentrations, maintains a cyclic and thus predictable pattern of bleeding, and allows a rapid return to ovulation after stopping ring use. The clinical development of vaginal rings was therefore started on the basis that vaginal rings could be an effective and convenient method for the delivery of contraceptive hormones. (Once a month, ease of use, control leading to freedom)

dosering Dagelijkse afgifte: 15 µg ethinylestradiol 120 µg etonogestrel Each NuvaRing is intended for one cycle of use. The regimen for each cycle is 3 weeks of continuous ring use, followed by a 1-week ring-free period. Each ring releases 15 μg ethinylestradiol and 120 μg etonogestrel per day over the 3-week ring-use period.

gebruik 1 ring per cyclus - 3 weken ring in - 1 week ring uit Each NuvaRing is intended for one cycle of use. The regimen for each cycle is 3 weeks of continuous ring use, followed by a 1-week ring-free period. Each ring releases 15 μg ethinylestradiol and 120 μg etonogestrel per day over the 3-week ring-use period.

Farmacokinetisch profiel van EE en ENG NuvaRing Farmacokinetisch profiel van EE en ENG After insertion of NuvaRing, hormone concentrations sufficient to achieve ovulation inhibition are reached within the first day of use. The maximum serum concentrations of ENG and EE are both reached within one week. It takes slightly longer for ENG to reach its maximum serum concentration than EE because ENG is extensively bound to sex hormone-binding globulin (SHBG), which itself increases under the influence of EE (SHBG also reaches its maximum level within one week). In contrast to oral contraceptives, maximum hormone concentrations with NuvaRing are reached only once during the 3 weeks of ring use. After reaching their maximum levels, the concentrations of ENG and EE start to decline in a gradual and linear manner. Timmer & Mulders, Clin Pharmacokinet, 2000;39:233–42

Farmacokinetisch profiel NuvaRing en 30 EE/150 DSG COC Css OC Css OC When the pharmacokinetic profiles of ENG and EE during NuvaRing use are compared with those of a COC containing 30 µg EE and 150 µg desogestrel (30 EE/150 DSG), the following can be concluded: The mean ENG concentration with NuvaRing is similar to the average concentration (Css) during 30 EE/150 DSG COC use. Therefore, the systemic exposure to ENG is similar for NuvaRing and the COC. However, the mean EE concentration with NuvaRing is about half of that with the COC containing 30 µg EE. Timmer & Mulders, Clin Pharmacokinet, 2000;39:233–42

NuvaRing klinisch ontwikkelings programma 3000 vrouwen 25,000 cycli 16 landen

Ervaringsproject Doel Ervaringen in de dagelijkse Nederlandse praktijk in kaart brengen Spiegelen van deze ervaringen aan de resultaten van het preregistratie onderzoek

Ervaringsproject Status Recrutering tot 1 juli 2003 Totaal aantal deelnemers aangemeld (nuvaring.net): 234 artsen 957 gebruiksters (inmiddels 15.000 vrouwen gestart) Project einde per 1 november 2003 Interim analyse per september 2003 Definitieve data Q1 - 2004

Ervaringsproject Leeftijd van de gebruikster

Ervaringsproject AC-methode vóór start NuvaRing

Ervaringsproject Duur van AC-gebruik (jaren)

Ervaringsproject Mening voorgaande AC-methode

Ervaringsproject Aantal maal switch van voorgaande AC-methode

Ervaringsproject Tampongebruik tijdens menses?

Contraceptieve effectiviteit Europese studie Zwangerschappen Cycli Pearl Index 95% CI ITT 6 12 109 0.65 0.24-1.41 (falen methode en gebruikster) PP 3 9 880 0.40 0.08-1.16 (falen methode) Roumen et al. Hum Reprod, 2001;16:469–75

Ervaringsproject Contraceptieve effectiviteit 1 zwangerschap (ring ongemerkt kwijtgeraakt)

Ervaringsproject Vragen Gemak van inbrengen en verwijderen Voelen van de ring door gebruikster en partner Cycluscontrole en onregelmatig bloedverlies Voordelen Bijwerkingen Tevredenheid

Ervaringsproject Gemak van inbrengen van de ring

Ervaringsproject Gemak van verwijderen van de ring

Ervaringsproject Voelen van ring bij coïtus door gebruikster

Ervaringsproject Voelen van ring bij coïtus door partner

Ervaringsproject Verwijderen ring tijdens coïtus

Cycluscontrole met (n=1182) 4.4% Irregular bleeding is vaginal bleeding occurring during the 3-week ring-use period (excluding any form of withdrawal bleeding). Irregular bleeding during the use of any hormonal contraceptive is generally considered undesirable. In the large one-year European efficacy study, irregular bleeding in women using NuvaRing was rare, occurring in only 2.6–6.4% of cycles; the average was 4.4% of women per cycle. In contrast to the pattern of irregular bleeding observed with COCs, the incidence of irregular bleeding was not considerably higher during the first cycles of NuvaRing use (illustrated in the next slide). The low incidence of irregular bleeding with NuvaRing is remarkable considering its ultra-low estrogen dose (15 μg EE). Roumen et al, Hum Reprod, 2001;16:469–75

Cycluscontrole met spotting en doorbraakbloeding Irregular bleeding is vaginal bleeding occurring during the 3-week ring-use period (excluding any form of withdrawal bleeding). Irregular bleeding during the use of any hormonal contraceptive is generally considered undesirable. In the large one-year European efficacy study, irregular bleeding in women using NuvaRing was rare, occurring in only 2.6–6.4% of cycles; the average was 4.4% of women per cycle. In contrast to the pattern of irregular bleeding observed with COCs, the incidence of irregular bleeding was not considerably higher during the first cycles of NuvaRing use (illustrated in the next slide). The low incidence of irregular bleeding with NuvaRing is remarkable considering its ultra-low estrogen dose (15 μg EE). Roumen et al, Hum Reprod, 2001;16:469–75

Ervaringsproject Onregelmatig bloedverlies voorafgaande AC- methode en tijdens ring

Ervaringsproject Voordelen ervaren bij gebruik van de ring

Bijwerkingen die leidden tot voortijdige beëindiging studie (15,1%) Percentage vrouwen (n=1145) Bijwerking Bijwerking gerelateerd aan de ring zelf 2,6% Hoofdpijn 2,1% Vaginaal ongemak 1,0% Tijdens het Europese onderzoek besloot 15,1% van de vrouwen hun deelname te beëindigen vanwege de bijwerkingen. Daarbij ging het vooral om bijwerkingen die gerelateerd waren aan het gebruik van de ring (2,6%), hoofdpijn (2,1%), vaginaal ongemak (1,0%) en misselijkheid (1,0%). Opmerkelijk is dat slechts een klein aantal vrouwen stopt met de behandeling vanwege problemen met de bloeding en vaginitis. Verder valt op dat de meeste vrouwen de deelname tijdens de eerste drie maanden beëindigden. Misselijkheid 1,0% Problemen met de bloeding 0,1% Vaginitis 0,6% Roumen et al. Hum Reprod, 2001;16:469–75

Ervaringsproject Belangrijkste reden om te stoppen met de ring

Ervaringsproject Tevredenheid gebruikster

Ervaringsproject Belangrijkste reden voor tevredenheid

Ervaringsproject Belangrijkste reden voor ontevredenheid

Ervaringsproject Conclusies (1) Bevindingen conform Europese preregistratie studie Redenen voorkeur: - 1 x per maand - lage oestrogeenbelasting Geschikt voor alle leeftijden Contraceptieve effectiviteit vergelijkbaar met pil

Ervaringsproject Conclusies (2) Eenvoudig in te brengen en te verwijderen Uitstekende cyclus controle Weinig oestrogeengerelateerde bijwerkingen Weinig coïtus problemen 4% stopt i.v.m ringgerelateerde problemen Hoge tevredenheid gebruikster en partner