Advances in the Pharmacotherapy of Contraceptives

Uche Anadu Ndefo, Pharm.D., BCPSAssistant Professor, Pharmacy PracticeCollege 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. www.cdc.gov

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 contraceptiveEarly 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®)

ContraceptionDays 1 – 7 Menstruati

on (3 – 7 days) Days 8 – 11

The lining of the womb

thickness in preparation for the egg

Day 14Ovulation

Days 18 – 25If

fertilization has not

taken place, the corpus

luteum fades away

Days 26 – 28

The uterine lining

detaches leading to menstruati

on

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™

EfficacyMulti-center, open-label, single arm studyn =1377 between 18 and 50 years of ageTreated for up to 20 cycles of 28 days13 pregnancies were reported during the studyContraceptive failure rate: 0.010

SafetyThe 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/m2

– 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)• 0.451 mg levomefolate calcium

– 4 light orange tablets, each containing • 0.451 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® ) + 0.451

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)• 0.451 mg levomefolate calcium,

– 7 light orange tablets, each containing • 0.451 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 0.451 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 2nd quarter

2011 (no name approved yet)

Emergency Contraception

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 2010 Glasier 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., BCPSAssistant Professor, Pharmacy PracticeCollege of Pharmacy & Health Sciences

Texas Southern University