Oral Contraceptive

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Contents 1 More Specific Terms 2 Introduction 3 Indications 4 Contraindications 5 Dosage 6 Pharmacokinetics 7 Monitor 8 Adverse-effects 9 Drug-interactions 10 Mechanism-of-action 11 More General Terms 12 References

More Specific Terms

• biphasic oral contraceptive
• monophasic oral contraceptive
• quadraphasic oral contraceptive
• triphasic oral contraceptive

Introduction

• Two types are available:
• combination of estrogen & progestin

• estrogen is mestranol or ethinyl estradiol
• all low-dose OCs have ethinyl estradiol
• progestin is one of six derivatives of 19-nor- testosterone

• 2nd generation agents contain levonorgestrel [9]
• 3rd generation agents contain desogestrel & gestodene

• progestin only

Indications

• prevention of pregnancy#
• treatment of acne
• hyperandrogenic states & hirsutism
• premenstrual syndrome
• dysmenorrhea
• heavy menses
• endometriosis
  

• * reduced risk of epithelial ovarian cancer with oral contraceptives, esp those containing high-dose progestins {protective effect of progestins} [10]
  
• # may be less effective in overweight women ( BMI > 27) [17]
• # LoSeasonique effective in obese women as well as women with normal BMI [30]

Contraindications

• current or past thrombophlebitis or thromboembolic disease
• cardiovascular disease
• impaired liver function
• known or suspected endocrine-dependent tumors of the breast or uterus
• pregnancy
• hyperlipidemia

• familial hypertriglyceridemia (may precipitate pancreatitis)
• serum triglycerides > 250 mg/dL
• low-density lipoprotein ( LDL) cholesterol > 160 mg/dL

• hypertension (uncontrolled)
• stop 4 weeks prior to surgery [13]

• 2-4 fold increased risk of post-operative thrombosis

• Caution:

• smoking (if age is > 35 & patient smokes, oral contraceptives are contraindicated)
• obesity
• varicose veins
• diabetes mellitus: use ONLY in diabetics < 35 years of age who do NOT smoke
• AVOID in women with migraine syndrome
• hypertension (avoid in women > 35 with hypertension)

Dosage

• therapy is best begun with onset of menses

• OCs NOT fully effective for 1st week or more [15]

• Sunday-start packaging

• begin 1st pill on Sunday following onset of menses
• if menses begins on Sunday, start 1st pill on that day
• 1 tablet daily
• last 7 days of 28 day package are inert tablets

• MISSED dosages

• 1 missed tablet:

• take one as soon as you remember, or
• take two the next day

• 2 missed tablets:

• take 2 tablets as soon as remembered & continue with the next daily dose at the scheduled time
• take 2 tablets/day for the next 2 days
• use additional contraceptive methods for 7 days

• 3 missed tablets:

• start a new package on day 1 of the cycle after the last pill was taken, or
• start 7 days after the last pill was taken
• use additional contraceptive methods for the remainder of the cycle

• tricycle regimen

• three 21 day packs (monophasic) consecutively
• wait one week, then restart another cycle
• reduces number of periods

• do NOT insert vaginally* [8]

• * Cosmopolitan magazine 2001 or 2002 site 2 studies of vaginally inserted BCP; these studies used higher dose pills than those in common use

Pharmacokinetics

• 1st pass metabolism in liver
• conjugated in liver, excreted in the bile
• deconjugated by gut bacteria -> enterohepatic circulation
• at least one week of therapy is necessary for preventing conception
• efficacy depends upon degree of compliance
• monophasic:

• fixed doses of estrogen & progestin throughout the cycle

• biphasic

• amount of estrogen remains the same for the 1st 21 days
• decreased progestin:estrogen ratio in the 1st 2 weeks of the cycle allows endometrial proliferation
• increased ratio of progestin:estrogen in the 2nd 2 weeks of the cycle allows secretory development

• triphasic [5]

• estrogen remains the same or varies throughout the cycle
• progestin varies

Monitor

• pelvic & breast exams NOT necessary prior to initiation of OCs [7]
• onset of menopause

• check hormone levels on 7th day of pill-free interval
• serum estradiol < 25 pg/mL & FSH/ LH ratio of > 1 indicates menopause
• switch to hormone replacement therapy

Adverse-effects

• due to estrogens

• increased risk of thromboembolism

• risk 9-18/100,000/year [18]
• increases risk 14-fold with air-travel [14]
• risk higher for oral contraceptives also containing progestin [29]

• risk higher for drospirenone than levonorgestrel (OR=2.4-3.3) [28]

• increased risk of coronary artery disease

• increased risk of MI with 2nd generation agents [9]
• risk is minimal with 3rd generation agents [9]

• increased risk of stroke
• increased frequency & severity of migraine headaches
• increased risk of hepatic adenoma
• post-pill amenorrhea

• due to progestins

• hair loss

• other

• nausea/vomiting
• weight gain
• depression
• may increase risk of cervical cancer [11]
• NO increase risk of breast cancer [12]
• may increase risk of urinary incontinence [23]
• accelerates HIV progression [25]
• no increase in mortality; may confer benefit [26]
  
• drug adverse effects of hormonal contraception

Drug-interactions

• agents which decrease effectiveness of OC

• antibiotics

• rifampin [19]
• griseofulvin
• inhibition of gut bacteria mediated deconjugation & entero-hepatic circulation of estrogen

• antiviral agents

• ritonavir [19]

• anticonvulsants

• barbiturates
• phenytoin
• lamotrigine increases metabolism of OCs [19]

• St John's wort [19]

• agents which increase effectiveness & toxicity of OCs

• antidepressants
• beta blockers
• corticosteroids
• theophylline
• retroviral protease inhibitors
• clarithromycin
• non-nucleoside reverse transcriptase inhibitors
• ketoconazole
• rifampin
• rifabutin
  

• drug interaction(s) of beta-adrenergic receptor antagonists with oral contraceptives

Mechanism-of-action

• combination OCs inhibit ovulation by:

• inhibition of GnRH secretion
• inhibition of mid-cycle LH surge

• progestin only products work by:

• altering cervical mucus
• progestational effect on the endometrium
• suppresses ovulation in some patients

More General Terms

• contraceptive
• pharmacologic combination

References

1. Stedman's Medical Dictionary 27th ed, Williams & Wilkins, Baltimore, 1999.
2. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
3. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 242-43
4. Medical Knowledge Self Assessment Program (MKSAP) 11, American College of Physicians, Philadelphia 1998
5. Prescriber's Letter 7(7):39 2000
6. Prescriber's Letter 7(9):52 2000
7. Journal Watch 21(11):85, 2001 Stewart FH et al Clinical breast and pelvic examination requirements for hormonal contraception: Current practice vs evidence. JAMA 285:2232, 2001 PMID: [1]
8. Prescriber's Letter 9(2):9 2002
9. Journal Watch 22(3):21-22, 2002 Tanis BC et al Oral contraceptives and the risk of myocardial infarction. N Engl J Med 345:1787, 2001 PMID: [2]
10. Journal Watch 22(5):39, 2002 Schildkraut JM et al Impact of progestin and estrogen potency in oral contraceptives on ovarian cancer risk. J Natl Cancer Inst 94:32, 2002 PMID: &dopt=Abstract
11. Journal Watch 22(9):74, 2002 Munoz N et al Role of parity and human papillomavirus in cervical cancer: the IARC multicentric case-control study. Lancet 359:1093, 2002 PMID: [3]
    - Moreno V et al Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study. Lancet 359:1085, 2002 PMID: [4]
12. Journal Watch 22(15):120-21, 2002 MarchBanks PA et al Oral contraceptives and the risk of breast cancer. N Engl J Med 346:2025, 2002 PMID: [5]
    - Davidson NE & Helzlsouer KJ Good news about oral contraceptives. N Engl J Med 346:2078, 2002 PMID: [6]
13. Prescriber's Letter 9(7):39 2002
14. Prescriber's Letter 11(2):8 2004 Detail-Document#: [7] (subscription needed) [8]
15. Prescriber's Letter 11(4):21 2004
16. Hormonal Contraception Prescriber's Letter 10(10):57 2003 Detail-Document#: [9] (subscription needed) [10]
17. Prescriber's Letter 12(2): 2005 Efficacy of Oral Contraceptives in Overweight Women Detail-Document#: [11] (subscription needed) [12]
    - Journal Watch 25(4):34-35, 2005 Holt VL, Scholes D, Wicklund KG, Cushing-Haugen KL, Daling JR. Body mass index, weight, and oral contraceptive failure risk. Obstet Gynecol. 2005 Jan;105(1):46-52. PMID: [13]
18. Prescriber's Letter 12(9): 2005 Ortho Evra and the Risk of Thromboembolism Detail-Document#: [14] (subscription needed) [15]
19. Prescriber's Letter 12(9): 2005 Oral Contraceptive (OC) Drug Interactions Detail-Document#: [16] (subscription needed) [17]
20. Prescriber's Letter 14(3): 2007 Concerns About the Newer Oral Contraceptives Detail-Document#: [18] (subscription needed) [19]
21. Prescriber's Letter 14(12): 2007 Hormonal contraception Detail-Document#: [20] (subscription needed) [21]
22. Prescriber's Letter 15(5): 2008 Hormonal Contraception in Older Women Detail-Document#: [22] (subscription needed) [23]
23. Townsend MK et al Oral contraceptive use and incident urinary incontinence in premenopausal women. J Urol 2009 May; 181:2170. PMID: [24]
    - Jackson SL and Fihn SD Exogenous estrogen and urinary incontinence. J Urol 2009 May; 181:1989. PMID: [25]
24. Prescriber's Letter 16(8): 2009 PATIENT HANDOUT: What I Need to Know About Missing Birth Control Doses CHART: Missed Doses of Hormonal Contraceptives COMMENTARY: Missed Doses of Hormonal Contraception GUIDELINES: Missed Hormonal Contraceptives: New Recommendations Detail-Document#: [26]
25. Stringer EM et al HIV disease progression by hormonal contraceptive method: Secondary analysis of a randomized trial. AIDS 2009 Jul 17; 23:1377. PMID: [27]
26. Hannaford PC et al. Mortality among contraceptive pill users: Cohort evidence from Royal College of General Practitioners' Oral Contraception Study. BMJ 2010 Mar 11; 340:c927. <PubMed> PMID: [28] <Internet> [29]
27. Prescriber's Letter 17(12): 2010 CHART: Hormonal Contraception CHART: Comparison of Oral Contraceptives Detail-Document#: [30] (subscription needed) [31]
28. Jick SS and Hernandez RK Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case- control study using United States claims data BMJ 2011; 342:d2151 <PubMed> PMID: [32] <Internet> [33]
    - Parkin L et al Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: nested case-control study based on UK General Practice Research Database BMJ 2011; 342:d2139 <PubMed> PMID: [34] <Internet> [35]
    - Dunn N The risk of deep venous thrombosis with oral contraceptives containing drospirenone BMJ 2011; 342:d2519 <PubMed> PMID: [36] <Internet> [37]
    - FDA Safety Alert: Posted 05/31/2011 Birth Control Pills Containing Drospirenone: Possible Increased Risk of Blood Clots [38]
29. Lidegaard O et al Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9 BMJ 2011; 343:d6423 <PubMed> PMID: [39] <Internet> [40]
    - Hannaford PC The progestogen content of combined oral contraceptives and venous thromboembolic risk BMJ 2011; 343:d6592 <PubMed> PMID: [41] <Internet> [42]
30. Westhoff CL et al. Body weight does not impact pregnancy rates during use of a low-dose extended-regimen 91-day oral contraceptive. Contraception 2012 Mar; 85:235. PMID: [43]
31. National Guideline Clearinghouse Drug interactions with hormonal contraception. Faculty of Family Planning and Reproductive Health Care ngc-guideline: [44]

oral contraceptive (OC)