Advances in the Pharmacotherapy of Contraceptives Uche Anadu Ndefo, Pharm.D., BCPS Assistant Professor, Pharmacy Practice College of Pharmacy & Health Sciences Texas Southern University

Financial Disclosure Statement I have no conflicts of interest in regards to this program

Learning Objectives At the end of this presentation, the audience will be able to: – Identify recent developments in the pharmacotherapy of contraceptives – Describe the pharmacology of novel contraceptives and new dosage forms – Discuss the place in therapy of these new agents

Contraception  Unwanted pregnancy is a significant public health problem  50% of pregnancies in the US are unintended  More than 1 in 5 US pregnancies end up in abortion  Goal of contraceptives is for pregnancies to be planned and desired  Oral contraceptives are the most popular  Used by 11.6 women in the US Unintended Pregnancy Prevention: Contraception.

Oral Contraceptives Oral contraceptives have a 0.3% failure rate with perfect use and an 8% failure rate with typical use Mechanism of Action – Suppresses ovulation – Causes cervical mucus changes that inhibit sperm penetration – Induces endometrial changes that reduce the likelihood of implantation

Oral Contraceptives Common ADEs – Headache, N/V, weight gain, breast tenderness Benefits of OCs – Acne – Reduction in benign breast disease – Dysmenorrhea – Premenstrual syndrome – Heavy bleeding – Reduction in risk of endometrial cancer – Reduction in risk of developing ovarian cysts

Oral Contraceptives Risks – Increased risk of stroke Smokers Women over the age of 35 Hypertensive women Migraine with aura – Thromboembolism Obesity – Increased risk of breast cancer?

History of Contraceptives 1960 First oral contraceptive approved in the US Envoid ® (contained 150 mcg of ethinyl estradiol) 1970s First IUD approved Lower doses of EE introduced (50 – 75 mcg EE) 1980s Biphasic (Ortho Novum ® 10/11) and triphasic (Ortho Novum ® 7/7/7) formulations introduced

History of Contraceptives 1990s First “mini” pill (progestin only) Injectable (Depo Provera ® ), Implant (Norplant) First emergency contraceptive Early 2000s The patch (Ortho Evra ® ) The ring (Nuvaring ® ) Extended cycle Ocs (Seasonale ® ) Late 2000s to Date No cycle OCs (Lybrel ® ) Low, low dose of EE The Implant (Implanon ® )

Contraception Days 1 – 7 Menstruation (3 – 7 days) Days 8 – 11 The lining of the womb thickness in preparation for the egg Day 14 Ovulation Days 18 – 25 If fertilization has not taken place, the corpus luteum fades away Days 26 – 28 The uterine lining detaches leading to menstruation

Natazia™ Generic Name – Estradiol valerate, dienogest Approved – May 2010 FDA Approved Indication – Contraception Cost/28 days – $98.59

Natazia™ Dosing – 2 dark yellow tablets containing 3 mg of estradiol valerate – 5 medium red tablets containing 2 mg of estradiol valerate and 2 mg of dienogest – 17 light yellow tablets containing 2 mg of estradiol valerate and 3 mg of dienogest – 2 dark red tablets each containing 1 mg of estradiol valerate – 2 white inert tablets

Natazia™  Efficacy  Multi-center, open-label, single arm study  n =1377 between 18 and 50 years of age  Treated for up to 20 cycles of 28 days  13 pregnancies were reported during the study  Contraceptive failure rate:  Safety  The most commonly reported ADEs were irregular bleeding, acne and weight gain Palacios et al. Eur J Obstet Gynaecol 2010:149(1):57-62

Natazia™ Place in Therapy – First four phasic oral contracpetive – Limited data on long term efficacy – Complex dosing schedule = difficulty with missed doses Patient Counseling – Should be taken on day 1 of menstrual cycle – A non-hormonal contraceptive (back-up) should be used during the first 9 days – Very difficult to catch up if you miss a dose

Lo Loestrin Fe™ Generic name – Norethindrone, ethinyl estradiol Approved – October 2010 FDA Approved Indication – Contraception Cost/28 days – $93.99

Lo Loestrin Fe™ Dosing – 24 blue tablets of 1 mg norethindrone acetate and 10 mcg ethinyl estradiol tablets – 2 white tablets of 10 mcg of ethinyl estradiol tablets – 2 brown tablets of 75 mg ferrous fumarate tablets Lowest dosage of estrogen (10 mcg) of any oral contraceptive currently available in the US market

Lo Loestrin Fe™ Efficacy – n = 1270 between age 18 – 35 – Excluded women with BMIs greater than 35 mg/m 2 – 2.92 pregnancyies per 100 over a year period – 28 pregnancies occurred after the onset of treatment and 7 days following last dose Safety – Most common were HA, N/V, bleeding irregularities and weight fluctuation

Lo Loestrin Fe™ Place in Therapy – Patients with ADEs with higher doses of estrogen – Questionable if there are less safety concerns with lower dose – Gap in efficacy?

Beyaz™ Generic name – Drospirenone, ethinyl estradiol, levomefolate Approved – September 2010 FDA Approved Indication – Contraception – Contraception + raise folate levels – Contraception + PMDD – Contraception + Acne  Cost/28 days $89.99

Beyaz™ Dosing – 24 pink tablets, each containing 3 mg drospirenone (DRSP) 0.02 mg ethinyl estradiol (EE) mg levomefolate calcium – 4 light orange tablets, each containing mg levomefolate calcium Efficacy – Used Yaz ® trials to prove efficacy for contraception, + PMDD, + acne vulgaris

Beyaz™ Efficacy – Duration – 24 weeks – 3 mg DRSP/0.02 mg EE (Yaz ® ) levomefolate (n=285) or Yaz ® alone (n=94) – The levomefolate group had higher plasma folate and RBC folate levels than the Yaz ® alone group Place in therapy – Women with a history of children with neural tube defects

Safyral™ Generic name – Drospirenone, ethinyl estradiol, levomefolate Approved – December 2010 FDA Approved Indication – Contraception – Contraception + raise folate levels Cost/28 days – $98.59

Safyral™ Dosing – 21 orange tablets, each containing 3 mg drospirenone (DRSP) 0.03 mg ethinyl estradiol (EE) mg levomefolate calcium, – 7 light orange tablets, each containing mg levomefolate calcium Efficacy – Contraception – used Yasmin ® trials to prove efficacy

Safyral™ Efficacy: Raise folate levels – n = 172 women between 18 and 40 years old – Treated for 24 weeks (additional 20 weeks of open-label Yasmin ® only) – Consumed food without folate fortification – Compared mg of levomefolate to Yasmin ® + folic acid – Only published results of the levomefolate arm compared to the open label portion – ADEs included PMS, HA, breast tenderness, N/V, abdominal pain

Low dose chewable 24/4 OC The only chewable OC on the US market currently is Femcon ® Fe – Dose: 0.4 norethindrone and 35 mcg EE Manufactured by Watson Pharmaceuticals 24/4 regimen – 24 tablets containing 0.8 mg norethindrone and 25 mcg EE – 4 tablets containing 75mg of ferrous fumarate Marketing is scheduled to begin 2 nd quarter 2011 (no name approved yet)

Emergency Contraception

Defined as the use of a drug or device as an emergency measure to prevent pregnancy after unprotected intercourse Common referred to “morning after pill” Used as a backup to contraception failure Should not be used routinely Should not be used as an ongoing form of birth control Pregnancy is a contraindication for the use of EC

Ella ®  Generic name  Ulipristal Acetate  Approved:  August 2010  FDA-Labeled Indication – Emergency contraception – Postcoital contraception Cost/tablet – $52.59

Ella ®  Mechanism of Action – A synthetic progesterone agonist/antagonist – Acts selectively on the human progesterone receptor and prevents progesterone from binding – When administered before ovulation, it postpones follicular rupture and therefore inhibits or delays ovulation – Alters the endometrium which affects implantation

Ella ® Brache et al. – Open label study – n = 1242 – Mean age: 24 – Dose: 30 mg of Ella – Observed rate of pregnancy: 2.2% Expected rate: 5.5% Glasier et al – Single blind study – n = 844 – Mean age: 25 – Ella 30 mg vs Levonorgestrel 1.5 mg – Observed rate of pregnancy: 1.9% vs. 2.6% Expected rate: 5.6% Brache et al. Human Reprod 2010Glasier et al. Lancet 2010

Ella ® ADEs: Headache, abdominal pain, nausea, dysmenorrhea, fatigue, dizziness Dosing and Administration – One tablet PO ASAP within 120 hours (5 days!) Place in Therapy – Rx Only – After 72 hours but before 120 hours – Cost compared to Plan B

Ella ® Patient Counseling – Available as Rx only – May be taken with or without food – May repeat doses if vomiting occurs within 3 hours of taken the tablet – May be taken any time during the menstrual cycle – Pregnancy should be ruled out with a test or history prior to initiation of treatment

Plan B ® One Step Generic Name – Levonorgestrel 1.5 mg Approved – July 2009 FDA Approved Indication – Emergency Contraception Cost/tablet – $49.99

Plan B ® One Step Dosing – Single dose emergency contraceptive – Formerly Plan B consisting of two levonorgestrel 0.75 mg tablets taken 12 hours apart Place in Therapy – Available OTC for consumers 17 years and older – Available by prescription only for women 16 years and younger – Some states do allow dispensing without Rx

NextChoice™ Generic to Plan B ® Approved – June 2009 Dosing – 2 tablets containing levonorgestrel 0.75 mg taken 12 hours apart Cost/2 tablets – $39.99

Pharmacoeconomic Considerations Regardless of the method used, preventing unintended pregnancy is highly cost effective Some choices are more cost effective than others Most oral contraceptives are generically available IUDs, implants and injectables are the most cost effective

Role of the Pharmacist Be familiar with current options available Educate patients on the various options available and their pros and cons Educate patient on possible adverse effects and complications Educate on missed doses and back-up contraception Advice patients that oral contraceptives for not prevent disease transmission

Advances in the Pharmacotherapy of Contraceptives Uche Anadu Ndefo, Pharm.D., BCPS Assistant Professor, Pharmacy Practice College of Pharmacy & Health Sciences Texas Southern University