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PHARM 562 Pharmacotherapeutics V Spring 2014 UW School of Pharmacy

PHARM 562 PHARMACOTHERAPEUTICS V

CONTRACEPTION

Lingtak-Neander Chan, PharmD, BCNSP School of Pharmacy University of Washington TEL : (206) 543-7987 Email : [email protected]

OBJECTIVES:

 Contrast the pharmacological differences among synthetic progestins and .  Understand the mechanism of action of emergency .  Determine the relative risks vs benefits of different hormonal contraceptive approaches in a woman according to her history and other factors.  Determine an alternative contraceptive method in a woman who experiences side effects from her existing contraceptive regimen.  Identify the clinically important interacting drugs that may alter the efficacy or safety of hormonal contraceptive agents and determine the management approaches to minimize the incidence of undesirable events.  Evaluate the alternative contraceptive options in the following special patient populations: a. Postpartum women b. Transplant recipients c. Bariatric surgery recipients d. Patients with HIV infection/AIDS e. Patients with epilepsy

Metabolic pathway of :

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Regulation of the .

PROGESTINAL EFFECT

ANDROGENIC EFFECT ESTROGENIC EFFECT

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I. PHARMACOLOGIC CHARACTERISTICS OF PROGESTINS.

PROGESTINS

NATURAL SYNTHETIC Progestins Progestins

Progesterone

SPIRONOLACTONE derivatives

PROGESTERONE derivatives derivatives

Pregnane 19-Norpregnane derivatives derivatives  acetate derivatives derivatives  acetate  Nestorone  Norethindrone   Norethindrone acetate   Ethynodiol diacetate   Norethynodrel   Norgestimate 

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General comparison among different synthetic progestins currently used in contraceptive agents:

-

estrogenic estrogenic androgenic mineralo

- - -

Progestin Estrogenic Effect Anti Effect Androgenic Effect Anti Effect Anti corticoid Progesterone - + - +/- + + Medroxyprogesterone - + +/- - + - acetate Nomegestrol - + - +/- - - * + + + - - - Levonorgestrel - + + - - - Norgestimate - + +(/-) - - - Drospirenone - + - + - +

* Norethisterones derivatives, including norethindrone, norethidrone acetate, ethynodial diacetate, norethinodrel

Relative progestogenic potency:

Ovulation Inhibition Transformation (mg/day PO) (mg/cycle) Progestin Progesterone 300 4200 Medroxyprogesterone acetate 10 60 Norethindrone 0.5 – 1.0 10 – 15 Norethindrone acetate 0.5 ~ 30 Levonorgestrel 0.05 6.0 Desogestrel 0.06 2.0 Norgestimate 0.2 7.0 Dienogest 1.0 6.0 Drospirenone 2.0 50

Pharmacokinetic Comparison

Oral Tmax Peak/Trough concentrations Progestin Micronized progesterone 300 mg 2 – 2.7 hrs 30/<2 ng/mL Medroxyprogesterone acetate ------Norethindrone 1 mg -- 1 – 2 hrs 16/<0.5 ng/mL Levonorgestrel 0.15 mg 72 – 100 % 1 – 3 hrs 3.5/<1 ng/mL

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II. PHARMACOKINETIC PROFILE OF SYNTHETIC AND PROGESTINS.

Estradiol valerate

Mestranol

Ethinyl estadiol:

CYP3A4, 2C9

UGT1A genes

 Oral bioavailability = 25 – 65 %  Tmax 1 to 6 hours  Sulfates undergo enterohepatic recirculation and ~30% deconjugated back to EE  T1/2 = 6 – 27 hrs  Inter-ethnic variation of PK reported

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Progestinogenic agents:

 Oral bioavailability: o Norethindrone 47 – 73 % o Levonorgestrel, gestodene, dienogest > 90 % o Other estranes 20 – 40 % o 3-keto-desogestrel 60 – 75 % o Drospirenone 70 – 80 %

 Tmax 1 to 3 hours -- Substrates of CYP 2C9, 2C19, and 3A4; SULF, and UGTs -- T1/2 : . Norethindrone: 8 – 12 hrs . Drospirenone: ~ 30 hrs . Other testosterone derivatives: 12 – 30 hrs

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III. PERICOITAL CONTRACEPTION. .

Mechanism of Action:

Most desirable treatment window:

A. Yuzpe method (non-FDA approved use)

 Variation of products to deliver comparable amount of EE + LNG http://ec.princeton.edu/questions/dose.html#dose

B. 30 mg (ella)

C. Levonorgestrel 0.75 mg x2

D. Levonorgestrel 1.5 mg x1

E. Other non-FDA approved, LNG-based regimens

F. Copper IUD

Glasier AF et al. Lancet 2010

Practical Issues:

1. What are the patient counseling points for EC? 2. How can the side effects of EC be reduced/minimized? 3. What happen if vomiting occurs after taking the dose?

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IV. CONSIDERATIONS BEFORE INITIATING HORMONAL CONTRACEPTION.

Refer to CDC/MMWR report 2013 for screening criteria.

Conditions where progestin-only methods are more appropriate (ACOG and WHO recommendation):  , especially those with focal neurologic signs such as an aura  Cigarette smoking and > 35 years of age  Obesity (ACOG, not WHO)  Hypertension, (especially uncontrolled) with vascular disease (or > 35 y.o. – ACOG)  Systemic lupus erythematosus with vascular disease, nephritis or antiphosphlipid antibodies  Diabetes with associated peripheral vascular disease (WHO)  History of thromboembolic diseases or thrombogenic mutations  Cerebrovascular disease (current or remote)  Coronary artery disease  Congestive heart failure  Known or suspected breast cancer  History of estrogen-dependent neoplasia  Undiagnosed abnormal genital bleeding (WHO)  Benign or malignant tumors, active liver disease, liver failure (WHO)  Hypertriglyceridemia (ACOG)  Less than 3 weeks postpartum

Risk for venous thromboembolic events in users of combined oral contraceptives:

Risk of associated with duration of use of oral contraceptive. Data from MEGA Case-Control Study (BMJ 2009)

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Duration of Use Odds Ratio (95% CI) No oral contraceptive use 1.0 ≤ 3 months 12.6 (7.1 – 22.4) 3 – 6 months 8.3 (4.7 – 14.5) 6 – 12 months 7.5 (4.7 – 12.2) 12 – 24 months 5.0 (3.4 – 7.4) 24 – 60 months 5.0 (3.7 – 6.8) > 60 months 5.2 (4.3 – 6.2)

 Using 30 mcg EE as reference, 20 mcg EE is associated with lower risk for VTE (OR 0.8; 95%CI 0.5 to 1.2), whereas 50 mcg EE is associated with higher risk for VTE (OR 1.9; 95%CI 1.1 to 3.4)

V. NON-ORAL ROUTE CONTRACEPTIVE APPROACHES

A. (IUD) a. Intrauterine copper contraceptive (ParaGard)  176 mg copper coiled along vertical stem + 68.7 mg copper on each side of the horizontal stem  Replace every 10 year (or sooner if indicated)

b. Levonorgestrel-releasing intrauterine system  A T-shaped polyethylene frame with a reservoir containing levonorgestrel 52 mg (Mirena) or 13.5 mg (Skyla)  Approved for (i) intrauterine contraception for up to 5 years (Mirena) or 3 years (Skyla); (ii) treatment of heavy menstrual bleeding (Mirena)  Recommended for women who have at least one child  Steady state levonorgestrel serum concentration between 150 – 200 pg/mL

B. Medroxyprogesterone acetate injectable suspension a. Depo-Provera intramuscular injection – 150 mg MPA deep IM Q13weeks b. depo-subQ provera 104 – 104 mg/ 0.65 mL SQ Q12 – 14 weeks

 Immediately effective if administered within 5 days of menstrual cycle  Return of fertility upon discontinuation: o IM : up to 22 months o SQ : 7 – 12 months  Absolute contraindications: (i) pregnancy; (ii) breast cancer  BLACKBOX WARNING: Loss of bone mineral density

 Non-contraceptive health benefits: o Decrease endometrial carcinoma o Reduce incidence of iron deficiency anemia o Decrease ovarian cysts o Decrease dysmenorrheal

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 Major adverse events: . Irregular bleeding/ spotting (50% first year 30 - 35 % second year) . 80% patients amenorrhea by year 3 . Weight gain (5.4, 8.1, 13.8 lb first 3 yrs respectively) (35 - 40 %) . . Hair problem . (16.5%) . Abdominal discomfort (11.2 %)

C. Etonogestrel implant

 Progestin-only hormonal subdermal implant for up to 3 years  68 mg etonogestrel (3-keto-desogestrel)  Release rate : 60 to 70 mcg/day in Week 5 to 6; decreases to approximately 35 to 45mcg/day at the end of the first year, to approximately 30 to 40mcg/day at the end of the second year, and then to approximately 25 to 30mcg/day at the end of the third year.

 Most common side effects: o Irregular menstrual flow/ bleeding . Infrequent bleeding (< 3 episodes/90 days): 33% . Amenorrhea (0 episode/90 days): 22% . Prolonged bleeding (Any 1 episode >14 days/90 days: 18% . Frequent bleeding (> 5 episodes/90 days): 7% o Headache: 25% o : 14.5 % o Weight gain: 13.7 % o Acne: 13.5 %

Drug interaction potential: Etonogestrel is a CYP3A4 substrate.

D. Etonogestrel (ETO)/ Ethinyl (EE) (NuvaRing)

 Contains 11.7 mg etonogestrel and 2.7mg ethinyl estradiol  Release rate 120 mcg ETO and 15 mcg EE/ day  Insert for 3 weeks followed by a week of ring-free period o Starting in a contraceptive-naïve woman – insert on day 1 o Switching from OC to the ring – switch any day o Switching from progestin-only product – the day for the next dose/ injection/ etc

 Major complications:

 Drug interactions

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E. Ethinyl estradiol/ transdermal system (Ortho Evra).

 Contains 6 mg norelgestromin/ 0.75 mg ethinyl estradiol. (designed to provide serum comparable to norgestimate 250 mcg/ EE 35 mcg)  Apply one patch and replace every 7 days x 3 weeks; week 4 = patch free period  Blackbox warning with cigarette smoking and cardiovascular risks; and increased risk of VTE (OR 1.2 – 2.2 over OCs with levonorgestrel /EE30 mcg and norgestimate/ EE35 mcg)

 Most common ADRs: . Breast symptoms 22 % . Headache 21 % . Application site discomfort 17 % . 16 % . Abdominal discomfort 8 % . 6 % . Mood swing or disorder 6 %

Practical Issues:

1. When is IUD, implant, patch, or the ring preferred over OC? 2. When is IUD, implant, patch, or the ring the least desirable option? 3. How do you manage spotting/BTB in women using copper IUD? 4. How do you manage drug interactions in women using non-OC hormonal devices?

VI. ORAL CONTRACEPTIVES (OCs).

a. Progestin-only oral contraceptive agents (aka mini-pills)

b. Combined hormonal oral contraceptive agents  Monophasic (21 + 7 placebo)  Monophasic – extended (24 + 4 placebo) (e.g., Yaz, Loestrin 24) (24 + 2 EE + 2 placebo) (e.g.,Lo Loestrin FE)  Monophasic – continuous (84 + 7 placebo) (e.g., Seasonale)  Multiphasic (21 + 5; 10 + 11, 7/7/7 or other combinations)  Multiphasic – extended (84 + 7EE) (e.g., Seasonique)

Other considerations:  50 mcg EE equivalent  Sub 50 mcg EE equivalent  20 mcg EE equivalent  Sub 20 mcg EE equivalent

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VII. MANAGEMENT APPROACH FOR MISSED DOSE(S).

Combined Oral Contraceptive Pills

 Take missed pill as soon as remembered and next pill at regular time  Use back-up method for one week if missed1-2 pills at the start of pack or 3 or more pills in the first 3 weeks of pack

Progestin-Only Pills

 Take missed pill as soon as remembered and next pill at regular time  Use back-up method for two days if pill is taken more than 3 hours past regular time

Transdermal Patch

 Use back-up method for one week if patch has been on more than 9 days, off more than 7 days, or falls off and is not reaffixed within 24 hours

Vaginal Ring

 Use back-up method for one week if ring has been in more than 5 weeks, out more than 7 days, or falls out and is not reinserted within 3 hours

VIII. MANAGEMENT CONSIDERATIONS FOR COMMON UNDESIRED EFFECTS. ` Undesired effects More likely with…. Alternatives… Acne

Breakthrough bleeding

Decreased libido

Depression

Hirsutism, Oily skin

Nausea

Weight gain

Menorrhagia, heavy flow

Tenderness of breasts

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CASE SYNOPSIS 1. Yolanda, a 24-year-old college student who is in good health, has been taking Ortho Tri-Cyclen for 3 months. She experiences pretty severe nausea in most of the mornings since starting her pills with several episodes of vomiting earlier this week. She prefers to continue to use the pill because it has significantly improved her acne and menstrual cramps.

CASE SYNOPSIS 2. Eva, a 35-year-old woman presents with a prescription of depot medroxyprogesterone acetate. She is 5’2” and 168 lbs. The medications on her profile include tacrolimus, MMF, prednisone, atorvastatin, amlodipine, citalopram, TMP/SMZ, acyclovir, fluconazole. She received a CRT 6 months ago.

CASE SYNOPSIS 3. Ashley, a 31-year-old woman, presents a prescription of itraconazole (regimen suggests treatment for onychomycosis) to your pharmacy and picks up her refill of Seasonique (LNG/EE 84-7).

CASE SYNOPSIS 4. Stefanie, a 32-year-old woman is scheduled to have elbow surgery secondary to a sport-related injury. She has celiac disease, IBS, and seasonal allergy. She is picking up her refills, with include amitriptyline, rifaximin, and Desogen® (DSG/EE 0.15/30). Would her risk of VTE from surgery be increased with concurrent OC use? Should she discontinue OC prior to surgery?

CASE SYNOPSIS 5. An ID doc would like to have your recommendation on choosing a contraceptive regimen for a 31-year-old woman with AIDS and hypercholesterolemia. Her current meds include Atripla (efavirenz + tenofovir + emtricitabine), atorvastatin, and sertraline.

CASE SYNOPSIS 6. Halle, a 25-year-old woman asks for your advice about contraception. She currently only uses condoms with her partner and she would be like to explore a more reliable method that she has more control. She is willing to take oral contraceptive pills on a daily basis. She typically experiences bloating and for 3 days before her menses and reports that her menstrual flow is heavy and lasts for 6 days. Her mother had a DVT when she was pregnant.

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CASE SYNOPSIS 7.

A 34-year-old woman G3P3 presents to your pharmacy with a prescription of carbamazepine 300 mg BID. She currently has the following active prescriptions on her profiles: OrthoCyclen QD x2 years Fluoxetine 20 mg QD x 6 years Lithium carbonate 300 mg TID x8 months Levothyroxine 0.025 mcg QD x3 months Vitamin D 1,500 IU QD carbonate 750mg BID w/ meals

You have a brief conversion with her about her medical history. You have learned that her last child is now 3 ½ years old. Her doctor told her that she has hypomania about 8 months ago and she has been taking lithium since. She thinks she is not as irritated since she had been taking lithium therapy. However, she has developed a hand tremor that is very bothersome to her – including not able to play the piano as she works as a part-time piano teacher. She is also having some acne. Her doctor is switching lithium to a different drug. She has also been diagnosed with hypothyroidism and has been taking levothyroxine for about 3 months.

A quick assessment of her physical appearance suggests that she is obese with a pear-shape body fat distribution. She looks like she is about 5’3” and close to 200 lbs. She has acne on her cheeks and the underside of her chin.

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