Break Free from the Pack with Break Free from the Pack with NuvaRingNuvaRing

By: Heather SandbulteBy: Heather Sandbulte

OverviewOverview

Generic Name: etonogestrel and ethinyl Generic Name: etonogestrel and ethinyl estradiol vaginal ringestradiol vaginal ring

New Administration of birth control by a New Administration of birth control by a vaginal ringvaginal ring

Invented by a company in the Invented by a company in the Netherlands, OrganonNetherlands, Organon

FDA approved in 2001 FDA approved in 2001 The efficacy and safety determined for The efficacy and safety determined for

women ages 15- 65 years old. women ages 15- 65 years old.

General StructureGeneral Structure

Vaginal RingVaginal RingNon-biodegradableNon-biodegradableFlexibleFlexibleTransparentTransparentOuter diameter: 54 mm Outer diameter: 54 mm

Combination Hormonal Combination Hormonal ContraceptiveContraceptive

Active Ingredients: Active Ingredients: Progestrone: etonogestrel Progestrone: etonogestrel

Ring Contains: 11.7 mgRing Contains: 11.7 mg Molecular Weight = 324.46Molecular Weight = 324.46

Estrogen: ethinyl estradiolEstrogen: ethinyl estradiol Ring Contains: 2.7 mgRing Contains: 2.7 mg Molecular Weight = 296.40Molecular Weight = 296.40

NuvaRing RegimenNuvaRing Regimen Insertion:Insertion:

Once a month exactly one-week Once a month exactly one-week after ring removal after ring removal

woman vaginally inserts the ring woman vaginally inserts the ring Various positionsVarious positions Body’s muscles hold ring in placeBody’s muscles hold ring in place

Removal: Removal: After 3After 3rdrd week of ring use week of ring use Hook ring and pull outHook ring and pull out

Ring-Free Week:Ring-Free Week: The 4The 4thth week week Body is free of vaginal ringBody is free of vaginal ring Withdrawal bleeding occursWithdrawal bleeding occurs

AdministrationAdministration

Absorbed by vaginal mucosaAbsorbed by vaginal mucosa Etonogestrel:Etonogestrel:

Released at a steady 0.120 mg/dayReleased at a steady 0.120 mg/day Bioavailability of 100%Bioavailability of 100% Binds: 32% to sex hormone binding globulin and 66% Binds: 32% to sex hormone binding globulin and 66%

to albuminto albumin Ethinyl estradiol:Ethinyl estradiol:

Released at a steady 0.015 mg/dayReleased at a steady 0.015 mg/day Bioavailability of 55.6%Bioavailability of 55.6% Binds non-specifically to albuminBinds non-specifically to albumin

Average Serum ConcentrationsAverage Serum Concentrations

1 week1 week 2 week2 week 3 week3 week

Etonogestrel Etonogestrel (pg/mL) (pg/mL)

15781578 14761476 13741374

Ethinyl-estradiol Ethinyl-estradiol (pg/mL) (pg/mL)

19.119.1 18.318.3 17.617.6

- Max Concentrations reached during week 1

- Concentrations slowly decrease

www.druglib.com

Overall Mechanism of ActionOverall Mechanism of Action

Combination of an estrogen with a progestin Combination of an estrogen with a progestin suppresses the hypothalamic-pituitary system suppresses the hypothalamic-pituitary system

Keep a steady dose of hormonesKeep a steady dose of hormones Inhibits spikes in hormone concentrationsInhibits spikes in hormone concentrations

The Mechanism Of Action of The Mechanism Of Action of Ethinyl EstradiolEthinyl Estradiol

Semisynthetic EstrogenSemisynthetic Estrogen

Binds to estrogen receptor complexBinds to estrogen receptor complex

Enter NucleusEnter Nucleus

Activates DNA transcription of gene Activates DNA transcription of gene for estrogenic cellular responsesfor estrogenic cellular responses

Increases hepatic synthesis of sex Increases hepatic synthesis of sex hormone binding globulin (32% of hormone binding globulin (32% of etonogestrel binds) and thyroid-etonogestrel binds) and thyroid-binding globulinbinding globulin

Suppresses release of follicle Suppresses release of follicle stimulating hormone (FSH) from stimulating hormone (FSH) from anterior pituitary anterior pituitary

The Mechanism of Action of The Mechanism of Action of EtonogestrelEtonogestrel

Synthetic form of progesteroneSynthetic form of progesterone Trick the body into thinking ovulation Trick the body into thinking ovulation

has already happenedhas already happened Binds to Progesterone receptors and Binds to Progesterone receptors and

activates progesterone receptor activates progesterone receptor mediated gene expressionmediated gene expression

Slowing the release of gonadotropin Slowing the release of gonadotropin releasing hormone (GnRH) from the releasing hormone (GnRH) from the hypothalmus and blunt the pre-hypothalmus and blunt the pre-ovulatory hormone surge of Luteinizing ovulatory hormone surge of Luteinizing hormone (LH)hormone (LH)

Human Reproduction ArticleHuman Reproduction Article

Clinical Study: Clinical Study: 40 subjects40 subjects average age of 28average age of 28 treatment of two 30 day cyclestreatment of two 30 day cycles Compared NuvaRing to Combined Oral Compared NuvaRing to Combined Oral

ContraceptivesContraceptives Evaluated:Evaluated:

Follicle stimulating hormone (FSH): stimulate a women to Follicle stimulating hormone (FSH): stimulate a women to produce a mature eggproduce a mature egg

Luteinizing hormone (LH): triggers the ovarian sac to rupture Luteinizing hormone (LH): triggers the ovarian sac to rupture and egg is releasedand egg is released

17beta-oestradiol (E2) and progesterone levels17beta-oestradiol (E2) and progesterone levels

Figure A:Figure A: NuvaRing had higher FSH NuvaRing had higher FSH

concentrationsconcentrations Levels low enough for efficiency Levels low enough for efficiency

Figure B:Figure B: NuvarRing had higher LH NuvarRing had higher LH

concentrationsconcentrations Levels low enough for efficiency Levels low enough for efficiency

Figure C:Figure C: E2 levels similar to COC but higher at E2 levels similar to COC but higher at

ring-free/pill-free periodsring-free/pill-free periods Figure D:Figure D:

Levels same for both groupsLevels same for both groups Overall Overall

NuvaRing concentration levels were NuvaRing concentration levels were either equal or higher than COCeither equal or higher than COC

kept fairly low to prevent pregnancykept fairly low to prevent pregnancy Complete inhibition & suppression of Complete inhibition & suppression of

ovulation after 3ovulation after 3rdrd week of NuvaRing use week of NuvaRing use is the same as that on day 21 of COCis the same as that on day 21 of COC

Duijkers

Additional Pregnancy PreventionAdditional Pregnancy Prevention

Cervical Mucus thickening Cervical Mucus thickening Increased viscosity slows sperm downIncreased viscosity slows sperm down

Clinical Trail on Follicular Diameter Clinical Trail on Follicular Diameter Combined Oral Contraceptive vs. NuvaRingCombined Oral Contraceptive vs. NuvaRing Results:Results:

Both had ovarian suppressionBoth had ovarian suppression Follicle size regress after NuvaRing InsertionFollicle size regress after NuvaRing Insertion Max size of 11 mm reached on the 2Max size of 11 mm reached on the 2ndnd day after ring-free period day after ring-free period

(smaller than the follicular size needed for pregnancy) (smaller than the follicular size needed for pregnancy) Remain small for remaining weeks of ring useRemain small for remaining weeks of ring use Relevance: Relevance:

Ovulation of small follicle less likely to succeed to a successful Ovulation of small follicle less likely to succeed to a successful pregnancy than larger folliclepregnancy than larger follicle

Duijkers

Phase III Clinical TrialPhase III Clinical Trial

Women Following Women Following ProtocolProtocol

OverallOverall

Treatment Treatment CyclesCycles

20,88920,889 23,29823,298

PregnanciesPregnancies 1010 2121

Large study of 2, 218 women

Evaluated whether pregnancy occurred or not

Small amount of pregnancies compared to total number of women

Hcp.nuvaring.com

Clinical Study on NuvaRing’s Clinical Study on NuvaRing’s Tolerability and AcceptanceTolerability and Acceptance

Performed in the Netherlands by Performed in the Netherlands by Department of Obstetric and Gynecology Department of Obstetric and Gynecology

1145 women began treatment1145 women began treatment806 women completed the study806 women completed the studyRing was removed by 90% of applicants Ring was removed by 90% of applicants

during the ring periodsduring the ring periodsQuestionnaire given to both participants Questionnaire given to both participants

that completed the study and the ones that that completed the study and the ones that did notdid not

Questionnaire's ResultsQuestionnaire's Results

800 completers and 280 discontinuers 800 completers and 280 discontinuers completed a questionnairecompleted a questionnaire

(Roumen)(Roumen)

Side EffectsSide Effects Most common:Most common:

Vaginal infections, irritations, and secretionsVaginal infections, irritations, and secretions HeadacheHeadache Changes in weight, nausea, and sexual desiresChanges in weight, nausea, and sexual desires

Major Risk: Major Risk: Associated with the circulatory systemAssociated with the circulatory system

Higher risk for myocardial infarction and thromboembolismHigher risk for myocardial infarction and thromboembolism Estrogen increases HDL cholesterol and progestin decreases HDL and Estrogen increases HDL cholesterol and progestin decreases HDL and

increases LDL levelsincreases LDL levels May increase risk of breast cancerMay increase risk of breast cancer

Decreases:Decreases: Acne Acne Ectopic pregnancyEctopic pregnancy Endometrial and ovarian cancersEndometrial and ovarian cancers Iron deficiency anemiaIron deficiency anemia Ovarian cystsOvarian cysts

Drug InteractionsDrug Interactions

Decrease NuvaRing’s Effectiveness:Decrease NuvaRing’s Effectiveness:Drugs that induce cytochrome P450 isozymesDrugs that induce cytochrome P450 isozymes

Cytochrome P450 metabolizes NuvaRing in the liverCytochrome P450 metabolizes NuvaRing in the liver

St. John’s WartSt. John’s Wart

Antibiotics with NuvaRingAntibiotics with NuvaRing Problem with oral contraceptive:Problem with oral contraceptive:

While in the gut, ethinyl estradiol is converted to While in the gut, ethinyl estradiol is converted to inactive metabolic formsinactive metabolic forms

The bacteria in the gut converts the metabolites back The bacteria in the gut converts the metabolites back into active forms of estrogen so they can be reabsorb into active forms of estrogen so they can be reabsorb (killing the bacteria will prevent this step from (killing the bacteria will prevent this step from occurring and the ethinyl estradiol will be excreted)occurring and the ethinyl estradiol will be excreted)

Numerous studies performedNumerous studies performed Result: Amoxicillin and Doxycycline do not have Result: Amoxicillin and Doxycycline do not have

any pharmacokinetic interactions with NuvaRingany pharmacokinetic interactions with NuvaRing Reason: It enters the bloodstream without being Reason: It enters the bloodstream without being

metabolized in the gut = no need for bacteriametabolized in the gut = no need for bacteria

NuvaRing CommercialNuvaRing Commercial

http://video.google.com/videosearch?http://video.google.com/videosearch?hl=en&q=NuvaRinghl=en&q=NuvaRing%20Commerical&um=1&ie=UTF-%20Commerical&um=1&ie=UTF-8&sa=N&tab=wv#8&sa=N&tab=wv#

Advertisement AnalysisAdvertisement Analysis Who is the ad targeting?Who is the ad targeting?

Women in their 20s or 30s wanting a hassle-free birth Women in their 20s or 30s wanting a hassle-free birth control method and one that is not old-fashion control method and one that is not old-fashion

The commercial effectively:The commercial effectively: Downplays the symptoms Downplays the symptoms Makes it feel like taking a pill each dayMakes it feel like taking a pill each day Mentions that it is as effective as the pill Mentions that it is as effective as the pill

The ad does not mention:The ad does not mention: The “ick factor” of NuvaRingThe “ick factor” of NuvaRing Due to a lack in routine, it may be more difficult to Due to a lack in routine, it may be more difficult to

remember remember What NuvaRing actually does except that it is 99% What NuvaRing actually does except that it is 99%

effective if taken properlyeffective if taken properly

Advertisement Analysis Cont.Advertisement Analysis Cont.

Is this a drug that should be advertised Is this a drug that should be advertised directly to consumers?directly to consumers? It may lower unplanned pregnanciesIt may lower unplanned pregnancies

Should the ad discuss what NuvaRing Should the ad discuss what NuvaRing does and its potential of lowering does and its potential of lowering unplanned pregnancies unplanned pregnancies Over three million of the 6.4 million Over three million of the 6.4 million

pregnancies in the United States each year pregnancies in the United States each year are unplannedare unplanned

Is NuvaRing a NecessityIs NuvaRing a Necessity

Is this form of birth control a necessity for Is this form of birth control a necessity for our fast-pace society?our fast-pace society?

Thank you for listening!Thank you for listening!

ReferencesReferences Androgens, Estrogens, and ProgestinsAndrogens, Estrogens, and Progestins. 05 April 2009. <http://images.google.com>. Path: estrogen . 05 April 2009. <http://images.google.com>. Path: estrogen

receptor.receptor. ““Birth Control Vaginal Ring (NuvaRing).” Planned Parenthood. 2 Nov. 2009. 7 March 2009. Birth Control Vaginal Ring (NuvaRing).” Planned Parenthood. 2 Nov. 2009. 7 March 2009.

<http://www.plannedparenthood.org/health-topics/birth-control/birth-control-vaginal-ring-nuvaring-<http://www.plannedparenthood.org/health-topics/birth-control/birth-control-vaginal-ring-nuvaring-4241.htm>.4241.htm>.

Bosch, Torie. “The Pill Killer.” Bosch, Torie. “The Pill Killer.” Slate MagazineSlate Magazine. 29 Sept. 2008. 3 March 2009 . 29 Sept. 2008. 3 March 2009 <http://www.slate.com/id/2201022/>.<http://www.slate.com/id/2201022/>.

Your Hormones and Your Fertility SignalsYour Hormones and Your Fertility Signals. FertilityFriend. 2004. Tamtris Web Services. 20 April 2009. . FertilityFriend. 2004. Tamtris Web Services. 20 April 2009. <http://www.fertilityfriend.com/HelpCenter/FFBook/ff_hormones_and_signs.html>.<http://www.fertilityfriend.com/HelpCenter/FFBook/ff_hormones_and_signs.html>.

Duijkers, Klipping, et al. “Ovarian Function with the contraceptive vaginal ring or oral contraceptive: a Duijkers, Klipping, et al. “Ovarian Function with the contraceptive vaginal ring or oral contraceptive: a randomized study.” randomized study.” Human ReproductionHuman Reproduction 27 Aug. 2004: Human Reproduction 2004. Dinox Medical 27 Aug. 2004: Human Reproduction 2004. Dinox Medical Investigations, Groenewoudseweg, The Netherlands. 20 March 2009 Investigations, Groenewoudseweg, The Netherlands. 20 March 2009 <http://humrep.oxfordjournals.org/cgi/content/full/19/11/2668>.<http://humrep.oxfordjournals.org/cgi/content/full/19/11/2668>.

Mahoney, Diana. “Two crossover studies: antibiotics don’t affect NuvaRIng.” Mahoney, Diana. “Two crossover studies: antibiotics don’t affect NuvaRIng.” Health Care IndustryHealth Care Industry. 2004. . 2004. International Medical News Group. 8 April 2009 International Medical News Group. 8 April 2009 <http://findarticles.com/p/articles/mi_m0CYD/is_14_39/ai_n6144479/>.<http://findarticles.com/p/articles/mi_m0CYD/is_14_39/ai_n6144479/>.

““Nuvaring.” Druglib.com. 2009. 10 March 2009 <http://druglib.com>.Nuvaring.” Druglib.com. 2009. 10 March 2009 <http://druglib.com>. ““NuvaRing Commerical.” youtube.comNuvaRing Commerical.” youtube.com ““Nuvaring Information.” Medications.com. 2007. Skylabs Inc. 10 March 2009 Nuvaring Information.” Medications.com. 2007. Skylabs Inc. 10 March 2009

<http://medications.com/drugs/nuvaring>.<http://medications.com/drugs/nuvaring>. NuvaRing.MDNuvaRing.MD. 2008. Schering-Plough Corporation. 15 March 2009 <http://hcp.nuvaring.com>. . 2008. Schering-Plough Corporation. 15 March 2009 <http://hcp.nuvaring.com>. Roumen, F.J.M.E., Apter, et al. “Efficacy, tolerability, and acceptability of a noval contraceptive vaginal ring Roumen, F.J.M.E., Apter, et al. “Efficacy, tolerability, and acceptability of a noval contraceptive vaginal ring

releasing etonogestrel and ethinyl oestradiol.” releasing etonogestrel and ethinyl oestradiol.” Human ReproductionHuman Reproduction March 2001. Atrium Medisch Centrum, March 2001. Atrium Medisch Centrum, Department of Obstetrics and Gynecology. The Netherlands. 25 March 2009. Department of Obstetrics and Gynecology. The Netherlands. 25 March 2009. <http://humrep.oxfordjournals.org/cgi/content/full/16/3/469?<http://humrep.oxfordjournals.org/cgi/content/full/16/3/469?ijkey=f4948eb594ab734c5d6ab2503e5316f62684859a>.ijkey=f4948eb594ab734c5d6ab2503e5316f62684859a>.