Break Free from the Pack with NuvaRing By: Heather Sandbulte

Overview Generic Name: etonogestrel and ethinyl estradiol vaginal ring Generic Name: etonogestrel and ethinyl estradiol vaginal ring New Administration of birth control by a vaginal ring New Administration of birth control by a vaginal ring Invented by a company in the Netherlands, Organon Invented by a company in the Netherlands, Organon FDA approved in 2001 FDA approved in 2001 The efficacy and safety determined for women ages years old. The efficacy and safety determined for women ages years old.

General Structure Vaginal Ring Vaginal Ring Non-biodegradable Non-biodegradable Flexible Flexible Transparent Transparent Outer diameter: 54 mm Outer diameter: 54 mm

Combination Hormonal Contraceptive Active Ingredients: Active Ingredients: Progestrone: etonogestrel Progestrone: etonogestrel Ring Contains: 11.7 mg Ring Contains: 11.7 mg Molecular Weight = Molecular Weight = Estrogen: ethinyl estradiol Estrogen: ethinyl estradiol Ring Contains: 2.7 mg Ring Contains: 2.7 mg Molecular Weight = Molecular Weight =

NuvaRing Regimen Insertion: Insertion: Once a month exactly one-week after ring removal Once a month exactly one-week after ring removal woman vaginally inserts the ring woman vaginally inserts the ring Various positions Various positions Body’s muscles hold ring in place Body’s muscles hold ring in place Removal: Removal: After 3 rd week of ring use After 3 rd week of ring use Hook ring and pull out Hook ring and pull out Ring-Free Week: Ring-Free Week: The 4 th week The 4 th week Body is free of vaginal ring Body is free of vaginal ring Withdrawal bleeding occurs Withdrawal bleeding occurs

Administration Absorbed by vaginal mucosa Absorbed by vaginal mucosa Etonogestrel: Etonogestrel: Released at a steady mg/day Released at a steady mg/day Bioavailability of 100% Bioavailability of 100% Binds: 32% to sex hormone binding globulin and 66% to albumin Binds: 32% to sex hormone binding globulin and 66% to albumin Ethinyl estradiol: Ethinyl estradiol: Released at a steady mg/day Released at a steady mg/day Bioavailability of 55.6% Bioavailability of 55.6% Binds non-specifically to albumin Binds non-specifically to albumin

Average Serum Concentrations 1 week 2 week 3 week Etonogestrel (pg/mL) Ethinyl-estradiol (pg/mL) Max Concentrations reached during week 1 - Concentrations slowly decrease

Overall Mechanism of Action Combination of an estrogen with a progestin suppresses the hypothalamic-pituitary system Combination of an estrogen with a progestin suppresses the hypothalamic-pituitary system Keep a steady dose of hormones Keep a steady dose of hormones Inhibits spikes in hormone concentrations Inhibits spikes in hormone concentrations

The Mechanism Of Action of Ethinyl Estradiol  Semisynthetic Estrogen  Binds to estrogen receptor complex  Enter Nucleus  Activates DNA transcription of gene for estrogenic cellular responses  Increases hepatic synthesis of sex hormone binding globulin (32% of etonogestrel binds) and thyroid- binding globulin  Suppresses release of follicle stimulating hormone (FSH) from anterior pituitary

The Mechanism of Action of Etonogestrel Synthetic form of progesterone Synthetic form of progesterone Trick the body into thinking ovulation has already happened Trick the body into thinking ovulation has already happened Binds to Progesterone receptors and activates progesterone receptor mediated gene expression Binds to Progesterone receptors and activates progesterone receptor mediated gene expression Slowing the release of gonadotropin releasing hormone (GnRH) from the hypothalmus and blunt the pre- ovulatory hormone surge of Luteinizing hormone (LH) Slowing the release of gonadotropin releasing hormone (GnRH) from the hypothalmus and blunt the pre- ovulatory hormone surge of Luteinizing hormone (LH)

Human Reproduction Article Clinical Study: Clinical Study: 40 subjects 40 subjects average age of 28 average age of 28 treatment of two 30 day cycles treatment of two 30 day cycles Compared NuvaRing to Combined Oral Contraceptives Compared NuvaRing to Combined Oral Contraceptives Evaluated: Evaluated: Follicle stimulating hormone (FSH): stimulate a women to produce a mature egg Follicle stimulating hormone (FSH): stimulate a women to produce a mature egg Luteinizing hormone (LH): triggers the ovarian sac to rupture and egg is released Luteinizing hormone (LH): triggers the ovarian sac to rupture and egg is released 17beta-oestradiol (E2) and progesterone levels 17beta-oestradiol (E2) and progesterone levels

Figure A: Figure A: NuvaRing had higher FSH concentrations NuvaRing had higher FSH concentrations Levels low enough for efficiency Levels low enough for efficiency Figure B: Figure B: NuvarRing had higher LH concentrations NuvarRing had higher LH concentrations Levels low enough for efficiency Levels low enough for efficiency Figure C: Figure C: E2 levels similar to COC but higher at ring-free/pill-free periods E2 levels similar to COC but higher at ring-free/pill-free periods Figure D: Figure D: Levels same for both groups Levels same for both groups Overall Overall NuvaRing concentration levels were either equal or higher than COC NuvaRing concentration levels were either equal or higher than COC kept fairly low to prevent pregnancy kept fairly low to prevent pregnancy Complete inhibition & suppression of ovulation after 3 rd week of NuvaRing use is the same as that on day 21 of COC Complete inhibition & suppression of ovulation after 3 rd week of NuvaRing use is the same as that on day 21 of COC Duijkers

Additional Pregnancy Prevention Cervical Mucus thickening Cervical Mucus thickening Increased viscosity slows sperm down Increased viscosity slows sperm down

Clinical Trail on Follicular Diameter Combined Oral Contraceptive vs. NuvaRing Combined Oral Contraceptive vs. NuvaRing Results: Results: Both had ovarian suppression Both had ovarian suppression Follicle size regress after NuvaRing Insertion Follicle size regress after NuvaRing Insertion Max size of 11 mm reached on the 2 nd day after ring-free period (smaller than the follicular size needed for pregnancy) Max size of 11 mm reached on the 2 nd day after ring-free period (smaller than the follicular size needed for pregnancy) Remain small for remaining weeks of ring use Remain small for remaining weeks of ring use Relevance: Relevance: Ovulation of small follicle less likely to succeed to a successful pregnancy than larger follicle Ovulation of small follicle less likely to succeed to a successful pregnancy than larger follicle Duijkers

Phase III Clinical Trial Women Following Protocol Overall Treatment Cycles 20,88923,298 Pregnancies1021  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 Tolerability and Acceptance Performed in the Netherlands by Department of Obstetric and Gynecology Performed in the Netherlands by Department of Obstetric and Gynecology 1145 women began treatment 1145 women began treatment 806 women completed the study 806 women completed the study Ring was removed by 90% of applicants during the ring periods Ring was removed by 90% of applicants during the ring periods Questionnaire given to both participants that completed the study and the ones that did not Questionnaire given to both participants that completed the study and the ones that did not

Questionnaire's Results 800 completers and 280 discontinuers completed a questionnaire 800 completers and 280 discontinuers completed a questionnaire(Roumen)

Side Effects Most common: Most common: Vaginal infections, irritations, and secretions Vaginal infections, irritations, and secretions Headache Headache Changes in weight, nausea, and sexual desires Changes in weight, nausea, and sexual desires Major Risk: Major Risk: Associated with the circulatory system Associated with the circulatory system Higher risk for myocardial infarction and thromboembolism Higher risk for myocardial infarction and thromboembolism Estrogen increases HDL cholesterol and progestin decreases HDL and increases LDL levels Estrogen increases HDL cholesterol and progestin decreases HDL and increases LDL levels May increase risk of breast cancer May increase risk of breast cancer Decreases: Decreases: Acne Acne Ectopic pregnancy Ectopic pregnancy Endometrial and ovarian cancers Endometrial and ovarian cancers Iron deficiency anemia Iron deficiency anemia Ovarian cysts Ovarian cysts

Drug Interactions Decrease NuvaRing’s Effectiveness: Decrease NuvaRing’s Effectiveness: Drugs that induce cytochrome P450 isozymes Drugs that induce cytochrome P450 isozymes Cytochrome P450 metabolizes NuvaRing in the liver Cytochrome P450 metabolizes NuvaRing in the liver St. John’s Wart St. John’s Wart

Antibiotics with NuvaRing Problem with oral contraceptive: Problem with oral contraceptive: While in the gut, ethinyl estradiol is converted to inactive metabolic forms While in the gut, ethinyl estradiol is converted to inactive metabolic forms The bacteria in the gut converts the metabolites back into active forms of estrogen so they can be reabsorb (killing the bacteria will prevent this step from occurring and the ethinyl estradiol will be excreted) The bacteria in the gut converts the metabolites back into active forms of estrogen so they can be reabsorb (killing the bacteria will prevent this step from occurring and the ethinyl estradiol will be excreted) Numerous studies performed Numerous studies performed Result: Amoxicillin and Doxycycline do not have any pharmacokinetic interactions with NuvaRing Result: Amoxicillin and Doxycycline do not have any pharmacokinetic interactions with NuvaRing Reason: It enters the bloodstream without being metabolized in the gut = no need for bacteria Reason: It enters the bloodstream without being metabolized in the gut = no need for bacteria

NuvaRing Commercial n&q=NuvaRing%20Commerical&um=1&ie =UTF-8&sa=N&tab=wv# n&q=NuvaRing%20Commerical&um=1&ie =UTF-8&sa=N&tab=wv#

Advertisement Analysis Who is the ad targeting? Who is the ad targeting? Women in their 20s or 30s wanting a hassle-free birth control method and one that is not old-fashion Women in their 20s or 30s wanting a hassle-free birth 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 day Makes 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 NuvaRing The “ick factor” of NuvaRing Due to a lack in routine, it may be more difficult to remember Due to a lack in routine, it may be more difficult to remember What NuvaRing actually does except that it is 99% effective if taken properly What NuvaRing actually does except that it is 99% effective if taken properly

Advertisement Analysis Cont. Is this a drug that should be advertised directly to consumers? Is this a drug that should be advertised directly to consumers? It may lower unplanned pregnancies It may lower unplanned pregnancies Should the ad discuss what NuvaRing does and its potential of lowering unplanned pregnancies Should the ad discuss what NuvaRing does and its potential of lowering unplanned pregnancies Over three million of the 6.4 million pregnancies in the United States each year are unplanned Over three million of the 6.4 million pregnancies in the United States each year are unplanned

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

Thank you for listening!

References Androgens, Estrogens, and Progestins. 05 April Path: estrogen receptor. Androgens, Estrogens, and Progestins. 05 April Path: estrogen receptor. “Birth Control Vaginal Ring (NuvaRing).” Planned Parenthood. 2 Nov March “Birth Control Vaginal Ring (NuvaRing).” Planned Parenthood. 2 Nov March Bosch, Torie. “The Pill Killer.” Slate Magazine. 29 Sept March Bosch, Torie. “The Pill Killer.” Slate Magazine. 29 Sept March Your Hormones and Your Fertility Signals. FertilityFriend Tamtris Web Services. 20 April Your Hormones and Your Fertility Signals. FertilityFriend Tamtris Web Services. 20 April Duijkers, Klipping, et al. “Ovarian Function with the contraceptive vaginal ring or oral contraceptive: a randomized study.” Human Reproduction 27 Aug. 2004: Human Reproduction Dinox Medical Investigations, Groenewoudseweg, The Netherlands. 20 March Duijkers, Klipping, et al. “Ovarian Function with the contraceptive vaginal ring or oral contraceptive: a randomized study.” Human Reproduction 27 Aug. 2004: Human Reproduction Dinox Medical Investigations, Groenewoudseweg, The Netherlands. 20 March Mahoney, Diana. “Two crossover studies: antibiotics don’t affect NuvaRIng.” Health Care Industry International Medical News Group. 8 April Mahoney, Diana. “Two crossover studies: antibiotics don’t affect NuvaRIng.” Health Care Industry International Medical News Group. 8 April “Nuvaring.” Druglib.com March “Nuvaring.” Druglib.com March “NuvaRing Commerical.” youtube.com “NuvaRing Commerical.” youtube.com “Nuvaring Information.” Medications.com Skylabs Inc. 10 March “Nuvaring Information.” Medications.com Skylabs Inc. 10 March NuvaRing.MD Schering-Plough Corporation. 15 March NuvaRing.MD Schering-Plough Corporation. 15 March Roumen, F.J.M.E., Apter, et al. “Efficacy, tolerability, and acceptability of a noval contraceptive vaginal ring releasing etonogestrel and ethinyl oestradiol.” Human Reproduction March Atrium Medisch Centrum, Department of Obstetrics and Gynecology. The Netherlands. 25 March Roumen, F.J.M.E., Apter, et al. “Efficacy, tolerability, and acceptability of a noval contraceptive vaginal ring releasing etonogestrel and ethinyl oestradiol.” Human Reproduction March Atrium Medisch Centrum, Department of Obstetrics and Gynecology. The Netherlands. 25 March