Colton Taylor, PharmD & Paul Hardy, PharmD

PGY1 Pharmacy Residents

Providence Alaska Medical Center

February 2020

WOMENS HEALTH: OVERVIEW OF COMMON PREVENTION AND TREATMENT STRATEGIES

DISCLOSURE

We have nothing to disclose

OBJECTIVES

By the end of the presentation, pharmacists should be able to:

Produce an initial oral contraceptive approach after assessing a sample patient case

Summarize pharmacologic fertility treatments currently available on the market

Outline a plan for hormone replacement therapy in a sample patient case

Using a sample FRAX and T-score, produce the appropriate pharmacologic intervention for osteoporosis and osteopenia

Describe common adverse effects and monitoring parameters for patients taking specific hormonal and targeted therapies

for treatment of breast cancer

OBJECTIVES (CONTINUED)

By the end of the presentation, pharmacy technicians should be able to:

Identify contraindications to estrogen-containing contraceptive therapy

Recognize fertility treatments currently available on the market

Describe common adverse effects and contraindications to various hormonal replacement therapies

Summarize the pharmacologic agents available to treat osteoporosis and osteopenia

Recognize proper handling and dispensing procedures for hormonal and targeted therapy medications used in the

treatment of breast cancer

THE

MENSTRUAL

CYCLE

Begins at menstruation and continues for approximately 14 days

Facilitates follicle development in the ovary

First 4 days

FSH levels rise

Follicles develop

Days 5 – 7

Dominant follicle releases estradiol and inhibin

Formation of receptors for FSH and LH

Synthesis of estradiol, progesterone, and androgen

FOLLICULAR PHASE

Brief – approximately 24 – 48 hrs

Follicular rupture and release of oocyte

With sustained levels of estradiol

Pituitary releases midcycle LH surge

Stimulates follicular maturation and ovulation

Conception most successful when intercourse occurs from 2 days prior to ovulation to the day of ovulation

OVULATION

Lasts 13 – 15 days

Luteinized follicles become corpus luteum

Synthesis androgen, estrogen, and progesterone

Progesterone

Maintains endometrial lining

Sustains implanted embryo and pregnancy

Maintains GnRH and gonadotropin release

If pregnancy occurs

hCG prevents regression of corpus luteum

Stimulates continued production of estrogen and progesterone for 6 – 8 weeks

LUTEAL PHASE

PREGNANCY

HORMONES

Barriers or prevention of ovulation

Inhibit viable sperm from coming into contact with mature ovum

Creation of unfavorable uterine environment

Prevent fertilized ovum from implanting successfully in endometrium

METHODS OF CONTRACEPTION

Nonpharmacologic therapy

Periodic abstinence

Barrier techniques

Diaphragm*

Cervical cap*

Sponge*

Condom*

Spermicides*

↓ transmission of STD

Pharmacologic therapy

Spermicides*

Oral contraceptives

Transdermal contraceptives

Contraceptive rings

Long-acting injectable and implantable contraceptives

Uterine devices*

TYPES OF CONTRACEPTION

* Non-hormone therapy

NONPHARMACOLOGICAL

THERAPY

NONPHARMACOLOGIC

Periodic abstinence

Highly motivated individuals

Rely on physical changes

Barrier techniques

Motivation

Consistency

Correct use

Disadvantage(s) Higher failure rates

Counseling

Efficacy determined by barrier and spermicide

Some protection against STD

Associated with UTI, yeast infections, TSS

Diaphragm

Fitted by physician

Dome shaped cap

Place over cervix 6 hours before intercourse

Leave in at least 6 hours after

Cervical cap

Better tolerated

Thimble-shaped cap

Place over cervix ½ hour before intercourse

Leave at least 8 hours after but not > a total of 48 hr

DIAPHRAGM AND CERVICAL CAP

DIAPHRAGM AND CERVICAL CAP

98% effective when used in conjunction with other barrier methods

STD protection – latex only

Mineral-oil based vaginal drug formulations ↓ barrier strength of latex by 90% in 60

seconds

Female condom (Reality®)

Equally effective to diaphragm

Pregnancy rate 21%

CONDOMS

PHARMALOGICAL

CONTRACEPTION

Estrogens

COMPONENTS OF CONTRACEPTIVES

Progestins

• Ethinyl estradiol (EE)

• Mestranol

• Similar in activity

MECHANISM OF ACTION

Estrogens

FSH suppression

Progestins

LH suppression

Cervical mucus thickening

Inhibition of egg implantation Thin endometrial lining

ADVERSE EFFECTS

Estrogen excess

Nausea, breast tenderness, HA,

weight gain due to fluid

retention

↓estrogen

Consider progestin-only or IUD

Dysmenorrhea, menorrhagia,

uterine fibroid growth

↓estrogen

Consider extended-cycle or continuous regimen

Estrogen deficiency

Vasomotor symptoms,

nervousness, ↓ libido

↑ estrogen

Early-cycle (days 1-9)

breakthrough bleeding/spotting

↑ estrogen

Absence of withdrawal bleeding Exclude pregnancy

↑ estrogen for menses

Continue for amenorrhea

ADVERSE

EFFECTS

Progestin excess

↑ appetite, weight gain, bloating,

constipation

↓ progestin

Acne, oily skin, hirsutism ↓ progestin

Choose less androgenic progestin

Depression, fatigue, irritability ↓ progestin

Progestin deficiency

Dysmenorrhea, menorrhagia ↑ progestin

Consider extended-cycle or cotinuous

regimen

Consider progestin-only or IUD

NSAIDs for dysmenorrhea

Late-cycle (days 10-21)

breakthrough bleeding/spotting

↑ progestin

SERIOUS ADVERSE

EFFECTS

Sign Problems

A Abdominal Pain Gallbladder disease,

hepatic adenoma

C Chest Pain, Cough, SOB MI or PE

H Headache, Dizziness, Numbness,

Slurred Speak, Tingling in

extremities

Stroke, HTN,

migraine

E Eye problems; vision loss, blurring Stroke, HTN

S Severe leg pain DVT

ESTROGENS

• Ethinyl estradiol (EE)

• Mestranol

• Similar in activity

PROGESTINS

Vary in progestational

activity

Differ with respect to

estrogenic,

antiestrogenic and

androgenic effects

Inhibit ovulation to some degree

Inconsistent

Higher ectopic pregnancy rates

Irregular menses

Hirsutism

EXAMPLES OF PROGESTINS

Ethynodiol diacetate

Desogestrel*

Norgestimate*

Drosperinone*

Norethindrone

Norethindrone acetate

Norethynodrel

Norgestrel

Levonorgestrel

* Potent progestin, no estrogenic effect, less androgenic

“MINI-PILLS” - PROGESTERONE ONLY

28 days of active hormone

No estrogen = no estrogen side effects

Nausea

Fluid retention

Breast tenderness

Headaches

“MINI-PILLS” - PROGESTERONE ONLY

Lower doses of progestins than combination oral contraceptives

Less effective with “typical” use

Generally reserved for women who cannot take estrogens

MINI-PILLS – COUNSELING POINTS

Start on the first day of menses

Take at same time every day!!!

No inactive pills

Back up method for first 1 to 2 months

Back up method

Whenever ANY pills are missed

If a pill is more than 3 hours late

Some recommend midcycle

4 days pre/post possible ovulation

LONG-ACTING PROGESTINS

Sustained progestin exposure:

Blocks LH surge, preventing ovulation

Reduces ovum motility in fallopian tubes

Thins endometrium

Thickens cervical mucus

Depo-Provera ® (medroxyprogesterone acetate)

LONG-ACTING PROGESTINS

Depo-Provera® (medroxyprogesterone acetate)

150mg IM injection every 3 months

Gluteal or deltoid muscle

Administer within 5 days of onset of menses

New formulation of Depo-SubQ Provera 104®

SQ abdomen or thigh

LONG-ACTING PROGESTINS

Advantages

Estrogens intolerance

Women experiencing Premenstrual weight gain

Nausea

Acne

Hypertension, dyslipidemia, h/o VTE, or h/o SLE

Decreased risk of premenstrual bleeding, nausea, acne

May prevent PID due to mucus thickening

Does not increase blood pressure, risk of thromboembolism

May be used in patients with seizure disorders

SUBDERMAL PROGESTIN IMPLANTS

Nexplanon®

Etonogestrel

Replaced after 3 years

Menstrual irregularities and headaches

No reported effects on bone mineralization

Return to fertility 30 days after removal

COMBINATION ORAL

CONTRACEPTIVES

(COC)

Components

50mcg estrogen (35 mcg most common)

1mg progestin

21 “active” days; 7 hormone free days

84 “active” days; 7 hormone free days

COMBINATION ORAL PRODUCTS

Monophasic: Fixed dose of estrogen/progestin throughout cycle

Biphasic: Fixed estrogen dose/2 different progestin doses

Triphasic: Varying doses of estrogen/progestin with 3 distinct phases

Multi-Phasic: Fluctuating hormone doses throughout cycle

CURRENT COC FORMULATIONS

Estrostep®

Increasing increments of estrogen

Fixed amount of progestin

Designed to reduce SE

Mimic normal cycle

Loestrin® 24 Fe, Mircette®

Primarily combination tabs

Few tabs that are only estrogen

Designed to minimize hormonal fluctuations

MULTI-PHASE AGENTS

Seasonale®

84 days “active”/7 days “inactive”

0.15mg levonorgestrel/.03mg ethinyl estradiol

Only 4 withdrawal periods per year

Increased incidence of bleeding/spotting between periods versus 28 day cycle

Typically decreases with use

EXTENDED CYCLE ORAL CONTRACEPTIVES

EXTENDED CYCLE ORAL CONTRACEPTIVES

Seasonique®

91-day regimen

7 placebo pills replaced with ethinyl estradiol 0.01 mg

Continuous estrogen

Eliminate the hormone-free interval

Non-cyclic

Continuously for 365 days per year

Ethinyl estradiol and levonorgestrel

No withdrawal bleeding

# Pills

Missed

Week

Missed

Recommendation Back Up Method

(7 days)

1 1 Take 2 pills ASAP*

Finish pill pack

Yes

1 2 – 3 Take 2 pills ASAP

Finish pill pack

No

1 4 Skip placebo pills

Finish pill pack

No

2 – 4 1 – 2 Take 2 pills ASAP*

Finish pill pack

Yes

2 – 4 3 Start a new pill pack No

2 – 4 4 Skip placebo pills

Finish pill pack

No

5 Any Take 2 pills ASAP*

Start new pill pack

Yes

MISSED DOSES – CHECK PACKAGE INSERT!!!

* Use emergency

contraception if necessary

Absolute

Thrombophlebitis, thromboembolic disorders

Cerebral vascular disease

Coronary artery disease

Peripheral vascular disease

Markedly impaired liver function

Known or suspect breast CA, or other estrogen dependent

tumor

COCS - CONTRAINDICATIONS

Absolute (continued)

Undiagnosed abnormal vaginal bleeding

Known or suspected pregnancy

Smokers > 35 years of age

Migraine headache with focal aura

Uncontrolled hypertension

COCS - CONTRAINDICATIONS

CHOOSING THE RIGHT OC

Smoking

Progestin-only pills

No estrogen if smoke

> 15 cigs/day and

> 35 yr

If choose to use estrogen in a smoker,

use 20 mcg formulation

CHOOSING THE RIGHT OC

Diabetes Progestin effects carbohydrate

and lipid metabolism

Progestin might increase insulin resistance

CHOOSING THE RIGHT OC

Migraine Headaches

Estrogen related

Decrease estrogen component

Occur during placebo period

“Hormone Withdrawal Syndrome”

Shorten/eliminate hormone free period

Mircette®

Active pills for 3 cycles before taking inactive pills

If headaches persist, patients reviewed for non-hormonal causes

Migraine with aura should not use COC

Cancer

Ovarian and endometrial CA ↓ by 40 – 50%

Last for 15 yr after stopping OC

Currently benign breast CA not contraindication

Even with positive family history

Increased risk of cervical dysplasia

1. 28 yo female comes into the clinic wanting to know what the best option for contraception would be for her.

PMH: Acne, recurrent yeast infections, pulmonary embolism (occurred 3 years ago).

a) Seasonique

b) Mini-pill

c) Depo-Provera

d) IUD

ASSESSMENT QUESTION #1

2. Which of the following are common adverse effects associated with progesterone therapy? (select all that apply)

a) Sleepiness

b) Amenorrhea

c) Endometrial cancer

d) Headache

e) Weight change/gain

ASSESSMENT QUESTION #2

INFERTILITY

INFERTILITY

Inability to conceive after 12 months of unprotected sexual intercourse

Initial evaluation

Timing of intercourse

Modifiable risk factors

Smoking, alcohol, caffeine, weight, illicit drugs

Determine the cause

Semen analysis

Confirmation of ovulation

Documentation of tubal patency

CORRECTION OF IDENTIFIABLE CAUSE

Hyperprolactinemia (male and female cause)

Prolactin: ↑ levels can cause infertility

Primary treatment: dopamine agonist (cabergoline > bromocriptine)

Secondary treatment: surgery

Hypothyroidism (male and female cause)

Associated with changes in menstrual cycle or sperm production

Primary treatment: thyroxine

Lifestyle modification

Drug use, caffeine, weight, exercise, stress

OVULATORY DYSFUNCTION: CLOMIPHENE Clomiphene (Clomid®)

Initial treatment for most anovulatory infertile women

Induces ovulation in ~60% of women with PCOS

MOA: selective-estrogen receptor-modulator (SERM)

Competes with estradiol for estrogen receptors at the hypothalamus

Blocks estrogen negative feedback at the hypothalamus

↓

Increase in GnRH

↓

Release of more FSH and LH

↓

Stimulates ovaries

OVULATORY DYSFUNCTION: CLOMIPHENE

Adverse effects: generally well tolerated

Hot flashes (>10%)

Mild abdominal or pelvic discomfort (6%)

Vaginal dryness, mood swings (10%)

Less frequent: dizziness, fatigue, breast tenderness, HA

D/C if visual disturbances (<2%)

Contraindications

Uncontrolled thyroid or adrenal dysfunction

Primary ovarian failure or ovarian cysts

Abnormal uterine bleeding

Hepatic disease (hepatic metabolism)

Pregnancy (category X)

OVULATORY DYSFUNCTION: INSULIN-SENSITIZING

AGENTS

Polycystic ovary syndrome (PCOS)

Potential cause for ovulatory dysfunction

Hyperinsulinemia key contributor

Treatment

Weight loss, nutrition, and exercise

Insulin-sensitizing agents

Metformin and thiazolidinediones

First line therapy: Metformin 1500-2000 mg/day

May be combined with clomiphene

OVULATORY DYSFUNCTION: GONADOTROPINS

Gonadotropins

Both LH and FSH needed for ovulation

Formulations vary based on what is required for patient

LH + FSH

Highly purified FSH

Recombinant FSH

Effective for ovulation induction

Women with hypogonadism or PCOS

Unexplained infertility

Risks

Multiple gestation

Ovarian hyperstimulation

ASSESSMENT QUESTION #3

3. What is the first line treatment for Patients with ovulatory dysfunction?

a) Clomiphene

b) Insulin-sensitizing agents

c) Mini-pills

d) Gonadatropins

HORMONE

REPLACEMENT

THERAPY

HRT GUIDELINES

Endocrine Society

Treatment of Symptoms of Menopause: An Endocrine Society Clinical Practice Guideline. (2015)

American College of Obstetricians and Gynecologists

Management of Menopausal Symptoms (2016)

North American Menopause Society

The 2017 Hormone Therapy Position Statement of the North American Menopause Society (2017)

INDICATIONS FOR TREATMENT

Perimenopausal and menopausal treatment of:

Vasomotor symptoms:

Hot flashes

Palpitations

Emotional lability

Vulvovaginal Symptoms

Vaginal atrophy

Prevention, NOT treatment of osteoporosis

RISKS ASSOCIATED WITH HRT

Cardiovascular

Increased risk of venous thromboembolism and stroke

Consider American College of Cardiology (ACC)

10-year risk predictor tool when considering risks and

benefits of HRT

Endometrial/Breast Cancer

Caution with estrogen monotherapy in women with an

intact uterus

Encourage routine screening for breast cancer while on

therapy

Risks increase with HRT extending beyond 5 years

10-Year CVD

Risk

Is HRT

Treatment Ok?

<5% Yes

5-10% Yes

(transdermal)

>10% Consider

alternatives

AVAILABLE FORMULATIONS

OSTEOPOROSIS

OSTEOPOROSIS GUIDELINES

Endocrine Society:

Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Clinical Practice

Guideline (May 2019)

National Osteoporosis Foundation

Clinician’s Guide to Prevention and Treatment of Osteoporosis (Aug 2014)

UK National Osteoporosis Guideline Group

UK Clinical Guidelines for the Prevention and Treatment of Osteoporosis (Dec 2017)

Canada Medical Association

2010 Clinical Practice Guidelines for the Diagnosis and Management of Osteoporosis in Canada: Summary

(Nov 2010)

WHO SHOULD BE EVALUATED FOR OSTEOPOROSIS?

Indications for BMD Scan:

Women ≥ 65 y.o

Postmenopausal women 50-69 y.o with certain risk factors*

Men ≥ 70 y.o

Postmenopausal women, men ≥ 50 years old with an adult age fracture

*Risk Factors:

Comorbid medical conditions predisposed to bone loss

Concomitant medications implicated in bone loss

Indications for vertebral imaging:

Additional indications for vertebral imaging:

Low-trauma fracture age ≥ 50 years old

Historical height loss ≥ 1.5 inches

Prospective height loss ≥ 0.8 inches

Recent or ongoing long-term glucocorticoid therapy

T-Score ≤-1.0 to -1.4 ≤-1.5

Women (Age) ≥70 65-69

Men (Age) ≥80 70-79

HOW TO BUILD STRONG BONES

Daily Recommended Intake:

Calcium

1000 mg/day elemental calcium for women ≥51 y.o

1200 mg/day for men ≥71 y.o.

Vitamin D

800-1000 International Units/day (20-25 mcg/day) for adults

≥50 y.o.

WHO SHOULD RECEIVE PHARMACOLOGIC

TREATMENT FOR OSTEOPOROSIS?

Men and postmenopausal women ≥ 50 y.o with any of the following:

Hip or vertebral fracture

T-score ≤ -2.5

T-score between =1.0 and -2.5 AND one of the following:

≥ 3% 10-year hip fracture probability

≥ 20% 10-year osteoporosis-related fracture probability

PHARMACOLOGIC OPTIONS FOR TREATING OSTEOPOROSIS

TREATMENT OPTIONS FOR OSTEOPOROSIS

Figure A. Osteoporosis treatment

Algorithm adopted from Endocrine

Society guidelines.a

BISPHOSPHONATES

Drug (generic) Route Formulation Frequency Dose

Alendronate Oral • Tablet

• Effervescent Tablet

Weekly 70 mg (Treatment)

35 mg (Prevention)

Ibandronate Oral Tablet Monthly 150 mg

IV IV Q3 Months 3 mg

Risedronate Oral • Immediate-

Release Tablet

Daily 5 mg

Weekly 35 mg

Monthly 150 mg

• Delayed Release

Tablet

Weekly 35 mg

Zoledronic Acid IV IV Annually 5 mg (Treatment)

Every Other Year 5 mg (Prevention)

BISPHOSPHONATE PERTINENT INFORMATION

First-line treatment for osteoporosis

Administration concerns with esophageal irritation

Dose adjustment with renal dysfunction

Ibandronate lacks evidence for reducing hip or

nonvertebral fractures

Class-specific adverse effect:

Atypical Femoral Fractures (AFF)

Osteonecrosis of the Jaw (ONJ)

Risk increased >5 years therapy

Optimal treatment duration:

3-5 years

Up to 10 years based on response

Prolonged effect after termination of therapy

Consider bisphosphonate holiday:

After 5 years oral therapy

After 3 years IV therapy

To reduce risk of AFF

RECEPTOR ACTIVATOR OF NUCLEAR FACTOR KAPPA-B LIGAND

(RANKL) INHIBITOR

Denosumab: 60 mg SubQ Q6 Months

Don’t normally consider a drug holiday

Return to baseline bone turnover within 24 months of discontinuation

Re-assess after 5-10 years for ongoing therapy needs

May be used in impaired renal dysfunction

Caution on use in hypocalcemia

Possible patient preference

PARATHYROID HORMONE ANALOGS

Teriparitide: 20 mcg SubQ once daily

Abaloparatide: 80 mcg SubQ once daily

DO NOT EXCEED two years therapy

Risk of osteosarcoma noted in animal studies 49

Possible advantage over bisphosphonates in patients with HIGH fracture risk

OTHER THERAPIES FOR OSTEOPOROSIS

Selective Estrogen Receptor Modulators (raloxifene)

Estrogen replacement therapy

Calcitonin

ASSESSMENT QUESTION #4

4. Which of the following medications may contribute to or cause osteoporosis and osteoporotic fractures? (select

all that apply)

a) Chronic steroid therapy

b) Raloxifene

c) Calcitriol

d) Teriparitide

e) Methotrexate

f) Proton Pump Inhibitors

g) Exogenous estrogen therapy

ENDOCRINE

THERAPIES FOR

BREAST CANCER

AROMATASE INHIBITORS

Drugs in class:

Anastrozole 1 mg PO daily

Exemestane 25 mg PO once daily

Letrozole 2.5 mg PO once daily

AI-associated musculoskeletal syndrome (AIMSS)

Hormonal effects

ESTROGEN RECEPTOR ANTAGONISTS

Drugs in class:

Fulvestrant

Tamoxifen (Selective Estrogen Receptor Modulator -

SERM)

Thromboembolic risks

Hepatic effects

Hormonal/Endocrine adverse effects

Agonist vs antagonist effects

HANDLING OF ORAL ENDOCRINE THERAPIES

USP 800 live as of December 1st, 2019

Protection of patients and employees from delivery

to removal and excretion of hazardous waste

Ensure training opportunities and competency

assessments for:

Handling

Transport

Manipulation

Disposal

NIOSH HAZARDOUS DRUG CLASSIFICATION

ASSESSMENT QUESTION #5

5. Which of the following medications increases risk of endometrial hyperplasia? (select all that apply)

a) Raloxifene

b) Tamoxifen

c) Estradiol

d) Norgestimate

ASSESSMENT QUESTION #6

6. When counting anastrozole, pharmacy personnel should use equipment dedicated for hazardous drug use and

chemotherapy-rated gloves. (true or false)

a) True

b) False

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