경구용 피임제 최신학술적 접근

이미지약사

What we will be talking about today

• 경구 피임제 역사.• QOL를 높이는 Lifestyle drug.• 경구피임제의 피임 원리.• 주요 경구 피임약 종류 및 비교.• ADRs.• 경구 피임제의 임상적 이익.• DDIs.• 프로게스틴 종류.• FAQ – 임상연구 논문을 중심으로.

QOL: Quality of Life ADR: adverse reactionDDI : drug-drug interactionFAQ: Frequently asked questions

History• 1916- 간호사 마거릿 생어, 다산(多産)이 빈민층의 모자사망율을 높

인다는 것을 깨달은 산아제한운동가‘여성들의 수태하지 않을 권리’를 주장한 여성 운동가

• 1919 - 쉐링사는 토끼 실험을 통해 에스트로겐과 프로게스테론을주입하면 배란이 억제되는 현상을 관찰해 보고.

• 하지만 여성 피임이 비도덕적인 사회 분위기 -> 30여 년이나 지나피임약 개발 시도가 이루어짐.

• 1937 - discovery of effects of progesterone on ovulation

• 1940’s -Russell Marker isolates progesterone from Mexican yams

• 1951 - Luis Miramontes synthesizes 1st progestin(from wild yam)

• 1952 - 내분비학자 그레고리 핀커스 박사에게 자금을 지원하면서비로소 개발 시작.

• 1960 - FDA's Approval of the 1st OCP, Enovid

• 2009년 현재 전세계 여성 10억 명 이상 복용 중(UN 통계)

http://www.acs.org/content/acs/en/education/whatischemistry/landmarks/progesteronesynthesis.html http://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/SelectionsFromFDLIUpdateSerieson

FDAHistory/ucm092009.htm

How The Pill Became a Lifestyle Drug • Marketing decisions, rather than scientific innovations• Guided the development and positioning of OCPs in

recent years.• Stalled progress in contraceptive development• Fine-tuning of the market for oral contraceptives in the

1990s and 2000s. • Pitched in the United States as an individual solution,

rather than a public health strategy• Since 1990, the content of that message has changed,

reflecting a shift in the drug industry's view of the contraception business.

• Two factors contributed to bring about this change: first, the industry's move away from research and development in birth control and second, the growth of the class of medications known as lifestyle drugs.

Ref: How the pill became a lifestyle drug Watkins ES. AJPH.2012.300706. Epub 2012 Jun 14.

Combined model of action of estrogen and progestin

• Prevents ovulation• Thickens mucous in cervix• Thins endometrium

Types of OBCPs*

• Progestin-only Pill(POP):

mini pill (Not available in Korea)

• Combination Pill

- Monophasic Pills

- Multiphasic Pills :Biphasic/Triphasic pills:

- Extended-cycle pills (Not available in Korea)

*OBCP: Oral Birth Control Pills

Monophasic vs Multiphasic COCPs (WHO report)

• There is no evidence that multiphasic oral contraceptives (OCs) are safer or more effective than monophasic OCs.

• There is no justification at present to recommend multiphasic OCs in preference to monophasic OCs

Ref: Shah DS. Monophasic versus multiphasic oral contraceptives: RHL commentary (last revised: 23 June 2009). The WHO Reproductive Health Library; Geneva: World Health Organization.

• van Vliet HAAM, Grimes DA, Helmerhorst FM, Schulz KF. Biphasic versus monophasic oral contraceptives for contraception. Cochrane Database of Systematic Reviews; Issue 3, 2006.

• van Vliet HAAM, Grimes DA, Lopez LM, Schulz KF, Helmerhorst FM. Triphasic versus monophasic oral contraceptives for contraception. Cochrane Database of Systematic Reviews;Issue 3, 2006.

• van Vliet HAAM, Grimes DA, Helmerhorst FM, Schulz KF. Biphasic versus triphasic oral contraceptives for contraception. Cochrane Database of Systematic Reviews;Issue 3, 2006.

Missed pill advice(for OBCPs)

• ㅊㅊ1 pill을 잊은 경우 생각나는 즉시 바로 복용 No back up needed

첫1, 2 주

생각나는 즉시 잊은 2정 복용이어서 기존 스케줄대로

7일 back up needed필요시 ECs

3 pills을 잊은 경우

2 pills을 잊은 경우

휴약기 없이 new pack 시작 7일 back up needed

필요시 ECs

The development of progestogens.

norgestimate

Gestodene Partly androgenic (gonanes) powerful antiovulatory & progestomimetic

activity w/ low androgenic activity. X 3 potent > levonorgestrel as a progestin no estrogenic activity excellent cycle control with combined pills

Ref: Progress in combined oral contraception: gestodene, third generation progestogen. Belaisch J. REVUE FRANCAISE DE GYNECOLOGIE ET D OBSTETRIQUE. 1989 May; 84(5):455-9.

New Progestins• Derivatives of levonorgestrel, a gonane hormone

Gestodene is biologically active in its native form

Desogestrel must first be metabolized into its biologically active form

Norgestimate is already active, but it will be metabolized in part to levonorgestrel.

• Effective contraception @ lower doses• improvements in metabolic parameters :

lack of impact on BP, / a balanced effect on coagulation, ↓ impact on carbohydrate metabolism compared with earlier, higher- dose formulations.

• no negative effects on lipid and lipoprotein biosynthesis• ↑ Cycle control - ↓ BTB • ↓ minor side effects ↓dropout rate

The new era in oral contraception: pills containing gestodene, norgestimate, and desogestrel. London RS Obstet Gynecol Surv. 1992 Nov;47(11):777-82.

Newer Progestins

• Drospirenone - Rx only• 17 α -spirolactone derivative & a 17 α -spironolactone analogue • Antimineralocorticoid & antiandrogenic• cause elevated levels of potassium in the body, which may cause

serious heart conditions and other health concerns.• Also approved to treat symptoms of premenstrual dysphoric

disorder (PMDD), to treat moderate acne(by FDA)• Black box Warning: appears on all Yaz and Yasmin packaging.

“Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke. Additionally, there are numerous warnings associated with the use of Yaz including, but not limited to, venous and arterial thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism, stroke), hepatic neoplasia, gallbladder disease, and hypertension.”

DRSP /EE 3mg/20microg (24/4 day regimen): a review of its use in contraception, premenstrual dysphoric disorder and moderate acne vulgaris. Fenton C et al. Drugs. 2007;67(12):1749-65. http://www.fda.gov

FDA Warning Letters YAZ, YASMIN (FYI)

Yaz Lawsuit: - Blood clots, stroke and other dangerous side effects associated, - > 10,000 U.S. patients to file lawsuits against Bayer Pharmaceuticals.- During only a four year period between 2004 and 2008, the FDA received more than 50 reports of death of women who were taking Yaz or Yasmin.

http://www.drugwatch.com/yaz/lawsuit.phphttp://yazcenter.com/yaz-yasmin/yaz-statistics

Hormone dose-related ADR

Excess DeficiencyEstrogen Progestin Estrogen Progestin

• N/V• Bloating• Edema• HTN• Migraine • Headache• Breast Tenderness•↓ libido• Wt gain• Heavy menstrual

flow• Leukorrhea

•Acne•↑Appetite• Wt gain• Fatigue• HTN• Depression• Hirsutism• Vaginal

yeast infection

•Early cyclespotting• BTB• Amenorrhea• Vaginal

dryness

• Late BTB• Amenorrhea• Heavy

menstrual flow

BTB: Breakthrough bleeding

ADR Associated w/ Type ofHormonal Activity

Estrogenic Progestational Androgenic

GI trouble: BloatingN/VBreast FullnessBTB*IrritabilityHeadacheHTN

HeadacheBreast pain/TendernessHTN

Acne / oily skinWeight gainHirutismFatigueDepression

Ref:- Dickerson LM, Bucci KK. Contraception. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. New York, NY: McGraw-Hill; 2002;5:1445-1461- Edwards LA. An update on oral contraceptive options. Formulary. 2004;39:104-121. - Wickersham RM, Novak KK, eds. Drug Facts and Comparisons. St. Louis, MO: Wolters Kluwer Health, Inc.; 2005.

Drug Interaction Checker

http://reference.medscape.com/drug-interactionchecker

Can antibiotics decrease the effectiveness of birth control pills?• No back up methods needed the exception of

rifampin-like drugsDickinson BD et al.

Rifampin impairs the effectiveness of OCs. PK of other antibiotics have not shown any systematic interaction between antibiotics and OCs

FSRHWHO

No longer advises that additional precautions are required when using COCP w/ antibiotics that are not enzymeinducers. (such as rifabutin and rifampicin)

George G Zhanel et al.

Rifampin is the only antibiotic to date that has been reported to reduce plasma estrogen concentrations.

Drug interactions between oral contraceptives and antibiotics. Dickinson BD et al. Obstet Gynecol. 2001 Nov;98(5 Pt 1):853-60.

FSRH (Faculty of Sexual and Reproductive Healthcare) UK Guideline (update 2014 Antibiotic and OCs interactions : Is there a need for concern? George G Zhanel et al. Can J Infect Dis 1999;10(6):429-433.

Normal period vs Heavy period

Normal period

Blood loss : 20-60 ml (4-12 tsps). Bleeding can last up to 8 days,

but bleeding for 5 days is average.

Heavy period

Blood loss : ≥ 60-80 ml (≥ 1/2 teacupful). It’s difficult to measure the amount of blood

For practical purposes- Flooding through to clothes or bedding.- Need frequent changes of sanitary towels or tampons.

- You need double sanitary protection (tampons & towels).

- You pass large blood clots.

Menstrual diary, Period Blood Loss Chart

http://www.obgyn.wustl.edu/mm/files/MENSTRUALFLOWDIARY.pdf

What can be done about BTB?• Stay on schedule• Keep taking as directed• Track BTB in a calendar or diary• Ask HCP about taking a short pill-free break • If you smoke, ask HCP to help you quit • When to Be Concerned: Keep count of how many

pads you use in an hour or in a day • Causes of BTB include the following:- Hormonal imbalances : As your body adapts to

different levels of hormones- Missed doses

http://www.mayoclinic.org/healthy-lifestyle/birth-control/in-depth/womens-health/art-20044044?pg=2

How to Stop Nausea Caused By Birth Control

• Eat a light snack such as crackers / a piece of fruit when you take

your birth control.

• An empty stomach can cause or intensify feelings of nausea, and

that may be alleviated with a small amount of food.

Step 1

• Take @ night and assess if your nausea subsides.

• According to the student health services at Brown University, many

women experience more nausea when taking their pills in the

morning than at night.

Step 2

• Wait it out if your nausea is only intermittent and mild.

• Usually within a few weeks of beginning OCs method, your body adjusts

to the hormone levels and the nausea will go away.

Step 3

What are the early warning signs of serious problems?

• Serious problems are rare

• usually have warning signs.

• Disclaimer: Notify your HCP ASAP possible if you experience any of the following signs of a blood clot:

• Also inform your HCP about any onset of depression or yellowing of the skin or eyes (a sign of jaundice).

A: severe abdominal pain C: severe chest pain or shortness of breath (SOB)H: severe headaches E: eye problems such as blurred vision, blind spots, flashing lights S: severe and persistent leg pain in the calf or thigh.

Source: Hatcher RA et al (2003), adapted with permission

Absolute Contraindications to COCPs(WHO)

• Breastfeeding < 6 wks postpartum (using POP)• Smoking >35 yo. (> 15 cigarettes/day) • Hypertension (SBP >160, DBP > 100) • Vascular disease • Current/history of IHD* • Stroke• Complicated valvular heart disease (pulmonary

hypertension, atrial fibrillation, history of SBE**) • Multiple risk factors for arterial cardiovascular

disease • Migraine with aura (any age) , migraine > 35 yo

*Ischemic Heart Disease**subacute bacterial endocarditis

Absolute Contraindications to COCPs(WHO) Cont’d

• Current breast cancer

• Diabetes with complication (nephropathy, retinopathy, neuropathy)

• History of or acute DVT/PE

• Known thrombophilias

• DVT/PE on anticoagulant therapy

• Major surgery with prolonged immobilization

• SLE with positive/unknown aPA*

• Hepatitis / acute viral hepatitis

• Severe cirrhosis (decompensated)

• Hepatocellular adenoma /malignant hepatoma

Ref: The World Health Organization. Improving access to quality care in family planning: medical eligibility criteria for contraceptive use. Geneva: WHO 2004. * Antiphospholipid-protein antibodies

Is it true that birth control pills cause blood clots?

an almost tripled risk of venous blood clot compared to no use

Lower Risk: Higher Risk :

OR 95% CI

levonorgestrel 2.38 18 to 2.59

norethisterone 2.56 2.15 to 3.06

norgestimate 2.53 2.17 to 2.96

OR 95% CI

gestodene 3.64 3.00 to 4.43

desogestrel 4.28 3.66 to 5.01

drospirenone 4.12 43 to 4.96

Cyproterone acetate

4.27 3.57 to 5.11

Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases Yana Vinogradova, et al. BMJ2015; 350 doi: http://dx.doi.org/10.1136/bmj.h2135

OR: Odds ratioCI : Confidence Interval

FDA Drug Safety Communication

• Updated information about the risk of blood clots in women taking birth control pills containing drospirenone

• Posted on 09-26-2011

• FDA has concluded that drospirenone-containing birth control pills may be associated with a higher risk for blood clots than other progestin-containing pills.

How do OCs affect liver cancer risk?

• Rare / inconclusive

Shail Maheshwari, et al.

The evidence is inconclusive to establish a relation between OCs & the risk of HCC*.

Future studies should focus on the duration, intermittency, and recency of OC use.

JULIE R. PALMER, et al.

OC use is associated w/ benign hepatic tumors in young ♀But, the # of cases of liver cancer in the U.S. that are attributable to OC use is probably small, because liver cancer is extremely rare in the U.S.

La Vecchia C, et al. - ↑ in the risk of benign liver tumors.-Benign tumors can form as lumps in different areas of the liver -> a high risk of bleeding or rupturing. - However, these tumors rarely become malignant.

* hepatocellular carcinoma

OC and the risk of hepatocellular carcinoma. Maheshwari S et al. J Hepatol. 2007 Oct;47(4):506-13. Epub 2007 Apr 5. ORAL CONTRACEPTIVE USE AND LIVER CANCER. JULIE R. PALMER et al. Am J Epidemiol. 1989 Nov;130(5):878-82. Female hormones and benign liver tumors. La Vecchia C, et al. Digestive and Liver Disease 2006; 38(8):535–536.

Doesn’t taking OCPs increase my risk of breast cancer?

No clear evidence that OCP use for any duration of time ↑ a woman’s risk of breast cancer.

In 1996 a large meta-analysis involving > 53,000 women concluded that OCP users did not have a clear increase breast cancer risk.(54 studies, 25 countries)

OCPs may increase diagnosis and detection of existing Breast CA.

Hormonal & reproductive history factors that↑ the risk of breast CA- Beginning menstruation at an early age- Experiencing menopause at a late age- Later age at first pregnancy- Not having children at all

Ref: Breast cancer and hormonal contraceptives. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 1996;347(9017):1713-27

How do oral OCs affect cervical cancer risk?

International Collaboration of Epidemiological Studies of Cervical CA

2007 longer used OCs, the higher risk of cervical CA However, among women who stopped taking OCs, the risk tended to decline over time, regardless of how long they had used oral contraceptives before stopping

Moreno V, et al. 2002 X 4 Risk: long-term use of OCs (≥5yr.) W/ positive HPV DNA

Cervical cancer and hormonal contraceptives International Collaboration of Epidemiological Studies of Cervical CA. Lancet 2007; 370(9599):1609–1621.Effect of oral contraceptives on risk of cervical cancer in women with HPV* infection: the IARC multicentric case-control study. Moreno V et al.

*human papillomavirus

How do oral OCs affect endometrial cancer risk?

Alfred O Mueck, et al. 2011 Biological plausibility for a carcinoprotective effect

↓ in risk: about 50%.

The ESHRE Capri Workshop Group

2001 the protection lasts for up to 20yr. after stopping use

Weiderpass E 1999 ↓ in risk: 30% by short term use80% by long term(> 10 yr.)

long-lasting protection : 20 yr. Subsequent use of HRT** did not

modify these protective effect.

Oral contraception and risk of endometrial cancer. Alfred O Mueck et al.

Open Access Journal of Contraception 2011:2 127–136 Ovarian and endometrial function during hormonal contraception. The ESHRE

Capri Workshop Group. Hum. Reprod. (2001) 16 (7): 1527-1535. Hormonal contraception and Use of oral contraceptives and endometrial

cancer risk (Sweden). M C Pike et al. Cancer Causes Control. 1999 Aug;10(4):277-84.

* Hormone Replacement Therapy

How do oral contraceptives affect ovarian cancer risk?

*CASH Study 1987 년 ↓risk: the same regardless of the type or amount of estrogen or progestin in the pillthe protection lasts for up to 15 yr after stopping use

Hankinson SE, et al.(recent CASH Study)

1992 년 ↓risk by 10~12 % after 1 yr of use and by approx. 50 % after 5 yrs of use

Schildkraut JM et al. 2002 년 ↓risk: Hi potency> low potency of progestin

**SHARE STUDY 2005 년 no diff the risk between androgenic and nonandrogenic pills

• The reduction in risk of ovarian cancer associated with oral-contraceptive use. The CASH Study of theCDC and the National Institute of Child Health and Human Development. New England Journal of Medicine 1987; 316(11):650–655.

• A quantitative assessment of oral contraceptive use and risk of ovarian cancer.Hankinson SE, et al. Obstetrics and Gynecology 1992; 80(4):708–714

• Impact of progestin and estrogen potency in oral contraceptives on ovarian cancer risk. Schildkraut JM, Journal of the National Cancer Institute 2002; 94(1):32–38. • Androgenic progestins in oral contraceptives and the risk of epithelial ovarian cancer. Greer JB, et al.

Obstetrics and Gynecology 2005; 105(4):731–740.

*CASH: The Cancer and Steroid Hormone Study **SHARE: Steroid Hormones and Reproductions