womens health - home - alaska pharmacists association€¦ · prevent fertilized ovum from...
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Colton Taylor, PharmD & Paul Hardy, PharmD
PGY1 Pharmacy Residents
Providence Alaska Medical Center
February 2020
WOMENS HEALTH: OVERVIEW OF COMMON PREVENTION AND TREATMENT STRATEGIES
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DISCLOSURE
We have nothing to disclose
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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
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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
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THE
MENSTRUAL
CYCLE
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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
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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
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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
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PREGNANCY
HORMONES
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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
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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
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NONPHARMACOLOGICAL
THERAPY
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NONPHARMACOLOGIC
Periodic abstinence
Highly motivated individuals
Rely on physical changes
Barrier techniques
Motivation
Consistency
Correct use
Disadvantage(s) Higher failure rates
Counseling
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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
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DIAPHRAGM AND CERVICAL CAP
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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
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PHARMALOGICAL
CONTRACEPTION
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Estrogens
COMPONENTS OF CONTRACEPTIVES
Progestins
• Ethinyl estradiol (EE)
• Mestranol
• Similar in activity
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MECHANISM OF ACTION
Estrogens
FSH suppression
Progestins
LH suppression
Cervical mucus thickening
Inhibition of egg implantation Thin endometrial lining
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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
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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
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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
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ESTROGENS
• Ethinyl estradiol (EE)
• Mestranol
• Similar in activity
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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
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EXAMPLES OF PROGESTINS
Ethynodiol diacetate
Desogestrel*
Norgestimate*
Drosperinone*
Norethindrone
Norethindrone acetate
Norethynodrel
Norgestrel
Levonorgestrel
* Potent progestin, no estrogenic effect, less androgenic
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“MINI-PILLS” - PROGESTERONE ONLY
28 days of active hormone
No estrogen = no estrogen side effects
Nausea
Fluid retention
Breast tenderness
Headaches
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“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
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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
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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)
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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
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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
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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
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COMBINATION ORAL
CONTRACEPTIVES
(COC)
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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
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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
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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
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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
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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
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# 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
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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
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Absolute (continued)
Undiagnosed abnormal vaginal bleeding
Known or suspected pregnancy
Smokers > 35 years of age
Migraine headache with focal aura
Uncontrolled hypertension
COCS - CONTRAINDICATIONS
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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
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CHOOSING THE RIGHT OC
Diabetes Progestin effects carbohydrate
and lipid metabolism
Progestin might increase insulin resistance
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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
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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
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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
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INFERTILITY
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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
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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
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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
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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)
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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
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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
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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
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HORMONE
REPLACEMENT
THERAPY
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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)
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INDICATIONS FOR TREATMENT
Perimenopausal and menopausal treatment of:
Vasomotor symptoms:
Hot flashes
Palpitations
Emotional lability
Vulvovaginal Symptoms
Vaginal atrophy
Prevention, NOT treatment of osteoporosis
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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
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AVAILABLE FORMULATIONS
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OSTEOPOROSIS
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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)
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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
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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.
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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
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PHARMACOLOGIC OPTIONS FOR TREATING OSTEOPOROSIS
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TREATMENT OPTIONS FOR OSTEOPOROSIS
Figure A. Osteoporosis treatment
Algorithm adopted from Endocrine
Society guidelines.a
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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)
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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
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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
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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
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OTHER THERAPIES FOR OSTEOPOROSIS
Selective Estrogen Receptor Modulators (raloxifene)
Estrogen replacement therapy
Calcitonin
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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
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ENDOCRINE
THERAPIES FOR
BREAST CANCER
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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
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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
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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
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NIOSH HAZARDOUS DRUG CLASSIFICATION
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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
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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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REFERENCES
1. ACOG Practice Bulletin No. 141: management of menopausal symptoms. Obstet Gynecol. 2014; 123(1): 202-216.
2. Adler RA, El-Hajj Fuleihan G, Bauer DC, Camacho PM, Clarke BL, Clines GA, Compston JE, Drake MT, Edwards BJ, Favus MJ, Greenspan SL, McKinney R Jr, Pignolo RJ, Sellmeyer DE.
Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2016;
31(1): 16–35.
3. ASCVD Risk Estimator Plus. American College of Cardiology. Available from: http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/. Accessed Dec 2019.
4. Black DM, Rosen CJ. Postmenopausal osteoporosis. N Engl J Med. 2016; 374(3): 254–262.
5. Compston J, Cooper A, Cooper C, et al. UK clinical guidelines for the prevention and treatment of osteoporosis. Arch Osteoporos. 2017; 12(1): 43.
6. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporosis International. 2014; 25(10): 2359-2381.
7. Davies C, Godwin J, Gray R, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomized trials.
Lancet. 2011; 378(9793): 771-784.
8. Dawson-Hughes B, Tosteson ANA, Melton LJ, 3rd, National Osteoporosis Foundation Guide Committee et al. Implications of absolute fracture risk assessment for osteoporosis
practice guidelines in the U.S.A. Osteoporos Int. 2008;19(4):449–458.
9. Deco HOUZZ. (2017, June 3). Falling Pills [Video]. YouTube. https://www.youtube.com/watch?v=_lhGDSA9EW4.
10. Dipiro. Pharmacottherapy. 10th ed. Chapter 79.
11. Eastell R, Rosen CJ, Black DM, Cheung AM, Murad MH, Shoback D. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society clinical practice
guideline. J Clin Endocrinol Metab. 2019;104(5):1595-1622. doi: 10.1210/jc.2019-00221.
12. Ishikawa K, Nagai T, Sakamoto K, et al. High bone turnover elevates the risk of denosumab-induced hypocalcemia in women with postmenopausal osteoporosis. Ther Clin Risk Manag.
2016; 12: 1831–1840.
13. Kaunitz AM, Manson JE. Management of menopausal symptoms. Obstet Gynecol. 2015; 126(4): 859-876.
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REFERENCES (CONTINUED)
1. Kendler DL, Marin F, Zerbini CAF, et al. Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO): a multicentre, double-
blind, double-dummy, randomised controlled trial. Lancet. 2018; 391(10117): 230–240.
2. Kendler DL, McClung MR, Freemantle N, et al. Adherence, preference, and satisfaction of postmenopausal women taking denosumab or alendronate. Osteoporos Int. 2011; 22(6):
1725–1735.
3. Khosla S, Burr D, Cauley J, American Society for Bone and Mineral Research et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society
for Bone and Mineral Research. J Bone Miner Res. 2007;22(10):1470–1491. doi: 10.1359/jbmr.0707onj.
4. Kienle PC. Safe handling of hazardous drugs protects healthcare workers and patients. Available from: https://qualitymatters.usp.org/safe-handling-hazardous-drugs-protects-healthcare-
workers-and-patients. Accessed Dec 2019.
5. NIOSH List of antineoplastic and other hazardous drugs in healthcare settings, 2016. Available from: https://www.cdc.gov/niosh/docs/2016-161/pdfs/2016-161.pdf. Accessed Dec 2019.
6. Papaioannou A, Morin S, Cheung AM, et al. 2010 Clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary. CMAJ. 2010; 182(17):1864-1873.
7. Qaseem A, Forciea MA, McLean RM, Denberg TD; Clinical Guidelines Committee of the American College of Physicians. Treatment of low bone density or osteoporosis to prevent
fractures in men and women: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017; 166(11): 818–839.
8. Ross AC, Taylor CL, Yaktine AL et al (eds) Dietary reference intakes for calcium and vitamin D. National Academies Press (US), Washington (DC). Available from:
http://www.ncbi.nlm.nih.gov/books/NBK56070/. Accessed Dec 2019.
9. Sanchez AC, Alsina JC, Dueñas-Díez J-L (2006). Selective estrogen receptor modulators: A new brand of multitarget drugs. Available from: https://link.springer.com/book/10.1007%2F3-
540-34742-9#editorsandaffiliations. Accessed Dec 2019.
10. Sanchez CK, Rumbellow S. Hormone replacement therapy for menopausal symptoms. Women’s Health. 2018; 43(9): 21-26.
11. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. NEJM. 2003; 348: 2431-2442.
12. Stuenkel CA, Davis SR, Gompel A, et al. Treatment of symptoms of the menopause: An Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology & Metabolism. 2015;
100(110: 3975-4011.
13. The 2017 hormone therapy position statement of the North American Menopause Society. Menopause. 2017; 24(7):728-753.