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oral contraceptive (OC)

Two types are available: 1) combination of estrogen & progestin a) estrogen is mestranol, estetrol or ethinyl estradiol b) all low-dose OCs have ethinyl estradiol c) progestin is one of six derivatives of 19-nor-testosterone 1] 2nd generation agents contain levonorgestrel [9] - levonorgestrel with 20 ug estrogen associated with lower risk for pulmonary embolism, stroke, or MI, relative to 7 other combinations [39] 2] 3rd generation agents contain desogestrel & gestodene c) see Femlyv for orally disintegrating birth control pill 2) progestin only - norgestrel OTC first over the counter oral contraceptvie FDA-approved (7/23) Indications: 1) prevention of pregnancy# 2) treatment of acne 3) hyperandrogenic states & hirsutism 4) premenstrual syndrome 5) dysmenorrhea 6) heavy menses 7) endometriosis # may be less effective in overweight women (BMI > 27) [17] # LoSeasonique effective in obese women as well as women with normal BMI [30] Advantages: * reduced risk of epithelial ovarian cancer with oral contraceptives, esp those containing high-dose progestins (RR=0.72) [44] {protective effect of progestins} [10] * reduced risk of endometrial cancer (RR=0.68) [37,44] Contraindications: 1) current or past thrombophlebitis or thromboembolic disease 2) cardiovascular disease 3) impaired liver function 4) known or suspected endocrine-dependent tumors of the breast or uterus 5) pregnancy & 1st 40 days post-partum - generally safe with breastfeeding > 40 days post-partum [46] 6) hyperlipidemia a) familial hypertriglyceridemia (may precipitate pancreatitis) b) serum triglycerides > 250 mg/dL c) low-density lipoprotein (LDL) cholesterol > 160 mg/dL d) newer oral contraceptives have minimal effect on lipids & a lipid profile is not indicated prior to initiating an oral contraceptive [4] 7) hypertension (uncontrolled) [46] 8) migraine with aura (estrogen-containing contraceptives)* [4] 9) women > 35 years of age who smoke > 15 cigarettes daily (estrogen-containing contraceptives)* [4] 10) stop 4 weeks prior to surgery [13] - 2-4 fold increased risk of post-operative thrombosis * increased risk for stroke [4] Caution: 1) smoking - if age is > 35 years & patient smokes > 15 cigarettes/day, estrogen-containing are contraindicated - use progestin-only contraceptive [4,34] 2) obesity 3) varicose veins 4) diabetes mellitus: use ONLY in diabetics < 35 years of age who do NOT smoke 5) AVOID in women with migraine syndrome 6) hypertension (avoid in women > 35 with hypertension) Dosage: 1) therapy is best begun with onset of menses - OCs NOT fully effective for 1st week or more [15] 2) Sunday-start packaging a) begin 1st pill on Sunday following onset of menses b) if menses begins on Sunday, start 1st pill on that day c) 1 tablet daily d) last 7 days of 28 day package are inert tablets 3) MISSED dosages a) 1 missed tablet: 1] take one as soon as you remember, or 2] take two the next day b) 2 missed tablets: 1] take 2 tablets as soon as remembered & continue with the next daily dose at the scheduled time 2] take 2 tablets/day for the next 2 days 3] use additional contraceptive methods for 7 days c) 3 missed tablets: 1] start a new package on day 1 of the cycle after the last pill was taken, or 2] start 7 days after the last pill was taken 3] use additional contraceptive methods for the remainder of the cycle 4) tricycle regimen a) three 21 day packs (monophasic) consecutively b) wait one week, then restart another cycle c) reduces number of periods 5) discontinuation of oral contraceptive - amenorrhea can last up to 3 months - longer duration should be investigated 6) 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 Monitor: 1) pregnancy test prior to prescription of hormonal contraception if > 1 week after last menstrual period (all women) [4] 2) pelvic exam & breast exam NOT necessary prior to initiation of oral contraceptive [4,7] 3) lipid profile not indicated prior to initiation [4] 4) onset of menopause a) check hormone levels on 7th day of pill-free interval b) serum estradiol < 25 pg/mL & FSH/LH ratio of > 1 indicates menopause c) switch to hormone replacement therapy Pharmacokinetics: 1) 1st pass metabolism in liver 2) conjugated in liver, excreted in the bile 3) deconjugated by gut bacteria -> enterohepatic circulation 4) at least one week of therapy is necessary for preventing conception 5) efficacy depends upon degree of compliance 6) monophasic: - fixed doses of estrogen & progestin throughout the cycle 7) biphasic a) amount of estrogen remains the same for the 1st 21 days b) decreased progestin:estrogen ratio in the 1st 2 weeks of the cycle allows endometrial proliferation c) increased ratio of progestin:estrogen in the 2nd 2 weeks of the cycle allows secretory development 8) triphasic [5] a) estrogen remains the same or varies throughout the cycle b) progestin varies Adverse effects: 1) due to estrogens a) increased risk of venous thromboembolism (VTE) - 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] - all combined oral contraceptives increase risk of venous thrombosis - the magnitidue of increase depends both on the progestin & the dose of estrogen [35] - newer oral contraceptives containing desogestrel or drospirenone associated with a 4-fold risk increase [36]; absolute risk = 0.14%; NNH=714 - older contraceptives containing levonorgestrel* or norgestimate associated with a 2.5-fold risk increase[36]; absolute risk = 0.06%; NNH=1667 b) increased risk of arterial thromboembolism - increased risk of stroke (RR = 1.5-2.2) & myocardial infarction (RR = 1.3-2.3) (RR for 30-40 ug of ethinyl estradiol) [31] c) increased risk of coronary artery disease - increased risk of MI with 2nd generation agents [9] - risk is minimal with 3rd generation agents [9]* d) no excess risk for cardiovascular disease or mortality [45] e) increased frequency & severity of migraine headaches f) increased risk of hepatic adenoma g) post-pill amenorrhea 2) due to progestins - hair loss - progestin only pills do not increase risk of venous thromboembolism [32] - breakthrough bleeding common with progestin-only oral contraceptives [4] 3) other - nausea/vomiting - weight gain - depression - may increase risk of cervical cancer [11] - risk of breast cancer - increased risk of breast cancer (RR=1.10) [44] - NO increase risk of breast cancer [12] - may diminish risk of ovarian cancer & endometrial cancer without increasing risk for breast cancer [41] - may increase risk of urinary incontinence [23] - accelerates HIV progression [25] - becoming pregnant while using oral contraceptives does not increase risk of birth defects [38] - no increase in mortality; may confer benefit [26] - no excess risk for cardiovascular disease or mortality [45] - associated with new-onset depression [40] * levonorgestrel with 20 ug estrogen associated with lower risk for pulmonary embolism, stroke, or MI, relative to 7 other combinations [39] Drug interactions: 1) agents which decrease effectiveness of OC a) antibiotics 1] rifampin [19] 2] griseofulvin 3] inhibition of gut bacteria mediated deconjugation & entero-hepatic circulation of estrogen b) antiviral agents - ritonavir [19] c) anticonvulsants 1] barbiturates 2] phenytoin 3] lamotrigine increases metabolism of OCs [19] d) St John's wort [19] 2) agents which increase effectiveness & toxicity of OCs a) antidepressants b) beta blockers c) corticosteroids d) theophylline e) retroviral protease inhibitors f) clarithromycin g) non-nucleoside reverse transcriptase inhibitors h) ketoconazole i) rifampin j) rifabutin Mechanism of action: 1) combination OCs inhibit ovulation by: a) inhibition of GnRH secretion b) inhibition of mid-cycle LH surge 2) progestin only products work by: a) altering cervical mucus b) progestational effect on the endometrium c) suppresses ovulation in some patients Notes: - the American College of Obstetricians and Gynecologist recommends that oral contraceptives should be made available over the counter to improve access to contraception [43] - dispensing a full year supply of oral contraception improves adherence & reduces unwanted pregnancy [42]

Interactions

drug interactions

Specific

biphasic oral contraceptive Estetrol/drospirenone (Nextstellis) estradiol/ethinyl estradiol/ferrous fumarate/norethindrone ethinyl estradiol/ethynodiol diacetate (Kelnor) ethinyl estradiol/norethindrone/ferrous fumarate (Larin Fe) monophasic oral contraceptive quadraphasic oral contraceptive triphasic oral contraceptive

General

hormonal 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, 16, 17. American College of Physicians, Philadelphia 1998, 2012, 2015
  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: 11325325
  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: 11752354
  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: 11773280
  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: 11943256 - 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: 11943255
  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: 12087137 - Davidson NE & Helzlsouer KJ Good news about oral contraceptives. N Engl J Med 346:2078, 2002 PMID: 12087145
  13. Prescriber's Letter 9(7):39 2002
  14. Prescriber's Letter 11(2):8 2004 Detail-Document#: 200203 (subscription needed) http://www.prescribersletter.com
  15. Prescriber's Letter 11(4):21 2004
  16. Hormonal Contraception Prescriber's Letter 10(10):57 2003 Detail-Document#: 191010 (subscription needed) http://www.prescribersletter.com
  17. Prescriber's Letter 12(2): 2005 Efficacy of Oral Contraceptives in Overweight Women Detail-Document#: 210212 (subscription needed) http://www.prescribersletter.com - 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: 15625141
  18. Prescriber's Letter 12(9): 2005 Ortho Evra and the Risk of Thromboembolism Detail-Document#: 210902 (subscription needed) http://www.prescribersletter.com
  19. Prescriber's Letter 12(9): 2005 Oral Contraceptive (OC) Drug Interactions Detail-Document#: 210903 (subscription needed) http://www.prescribersletter.com
  20. Prescriber's Letter 14(3): 2007 Concerns About the Newer Oral Contraceptives Detail-Document#: 230303 (subscription needed) http://www.prescribersletter.com
  21. Prescriber's Letter 14(12): 2007 Hormonal contraception Detail-Document#: 231207 (subscription needed) http://www.prescribersletter.com
  22. Prescriber's Letter 15(5): 2008 Hormonal Contraception in Older Women Detail-Document#: 240508 (subscription needed) http://www.prescribersletter.com
  23. Townsend MK et al Oral contraceptive use and incident urinary incontinence in premenopausal women. J Urol 2009 May; 181:2170. PMID: 19296979 - Jackson SL and Fihn SD Exogenous estrogen and urinary incontinence. J Urol 2009 May; 181:1989. PMID: 19286197
  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#: 250811
  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: 19448528
  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. PMID: 20223876 http://dx.doi.org/10.1136/bmj.c927
  27. Prescriber's Letter 17(12): 2010 CHART: Hormonal Contraception CHART: Comparison of Oral Contraceptives Detail-Document#: 261207 (subscription needed) http://www.prescribersletter.com
  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 PMID: 21511805 http://www.bmj.com/content/342/bmj.d2151 - 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 PMID: 21511804 http://www.bmj.com/content/342/bmj.d2139 - Dunn N The risk of deep venous thrombosis with oral contraceptives containing drospirenone BMJ 2011; 342:d2519 PMID: 21511807 http://www.bmj.com/content/342/bmj.d2519.extract - FDA Safety Alert: Posted 05/31/2011 Birth Control Pills Containing Drospirenone: Possible Increased Risk of Blood Clots http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm257337.htm
  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 PMID: 22027398 http://www.bmj.com/content/343/bmj.d6423.full - Hannaford PC The progestogen content of combined oral contraceptives and venous thromboembolic risk BMJ 2011; 343:d6592 PMID: 22028481 http://www.bmj.com/content/343/bmj.d6592.extract
  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: 22067763
  31. Lidegaard O et al Thrombotic Stroke and Myocardial Infarction with Hormonal Contraception N Engl J Med 2012; 366:2257-2266June 14, 2012 PMID: 22693997 http://www.nejm.org/doi/full/10.1056/NEJMoa1111840 - Petitti DB Hormonal Contraceptives and Arterial Thrombosis - Not Risk-free but Safe Enough N Engl J Med 2012; 366:2316-2318June 14, 2012 PMID: 22694003 http://www.nejm.org/doi/full/10.1056/NEJMe1204769
  32. Mantha S et al Assessing the risk of venous thromboembolic events in women taking progestin-only contraception: a meta-analysis. BMJ 2012;345:e4944 PMID: 22872710 http://www.bmj.com/content/345/bmj.e4944
  33. American College of Obstetricians and Gynecologists Over-the-Counter Access to Oral Contraceptives http://www.acog.org/Resources_And_Publications/Committee_Opinions/Committee_on_Gynecologic_Practice/Over-the-Counter_Access_to_Oral_Contraceptives
  34. ACOG Committee on Practice Bulletins-Gynecology. ACOG practice bulletin. No. 73: Use of hormonal contraception in women with coexisting medical conditions. Obstet Gynecol. 2006 Jun;107(6):1453-72. PMID: 16738183
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  36. Vinogradova Y et al Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ 2015;350:h2135 PMID: 26013557 http://www.bmj.com/content/350/bmj.h2135 - Jick SS Fresh evidence confirms links between newer contraceptive pills and higher risk of venous thromboembolism. BMJ 2015;350:h2422 PMID: 26013974 http://www.bmj.com/content/350/bmj.h2422
  37. Collaborative Group on Epidemiological Studies on Endometrial Cancer. Endometrial cancer and oral contraceptives: an individual participant meta-analysis of 27,276 women with endometrial cancer from 36 epidemiological studies. The Lancet Oncology. Aug 5, 2015 PMID: 26254030 http://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045%2815%2900212-0.pdf
  38. Charlton BM et al Maternal use of oral contraceptives and risk of birth defects in Denmark: prospective, nationwide cohort study. BMJ 2016;352:h6712 PMID: 26738512 http://www.bmj.com/content/352/bmj.h6712
  39. Weill A, Dalichampt M, Raguideau F et al Low dose oestrogen combined oral contraception and risk of pulmonary embolism, stroke, and myocardial infarction in five million French women: cohort study. BMJ 2016;353:i2002 PMID: 27164970 Free PMC Article http://www.bmj.com/content/353/bmj.i2002 - Hannaford PC The vascular risks associated with combined oral contraceptives. BMJ 2016;353:i2544 PMID: 27165133 http://www.bmj.com/content/353/bmj.i2544
  40. Skovlund CW et al Association of Hormonal Contraception With Depression. JAMA Psychiatry. Published online September 28, 2016. PMID: 27680324 http://archpsyc.jamanetwork.com/article.aspx?articleid=2552796
  41. Michels KA, Brinton LA, Pfeiffer RM, Trabert B. Modification of the associations between duration of oral contraceptive use and ovarian, endometrial, breast, and colorectal cancers. JAMA Oncol 2018 Jan 18; PMID: 29346467 https://jamanetwork.com/journals/jamaoncology/article-abstract/2669779
  42. Judge-Golden CP, Smith KJ, Mor MK, Borrero S Financial implications of 12-month dispensing of oral contraceptive pills in the Veterans Affairs health care system. JAMA Intern Med 2019 Jul 8; PMID: 31282923 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2737751
  43. Isley M, MD, Allen RH American College of Obstetricians and Gynecologists' Committee on Gynecologic Practice Over-the-Counter Access to Hormonal Contraception ACOG Committee Opinion Summary, Number 788. Obstetrics & Gynecology: Oct 2019 - 134(4):886-887 https://journals.lww.com/greenjournal/Fulltext/2019/10000/Over_the_Counter_Access_to_Hormonal_Contraception_.41.aspx
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  45. Lou N Women on the Pill Have Comforting CVD Outcomes Years Down the Line. Oral contraceptive use not tied to excess cardiovascular disease, mortality. MedPage Today August 11, 2023. https://www.medpagetoday.com/cardiology/prevention/105860 - Dou W, Huang Y, Liu X et al Associations of Oral Contraceptive Use With Cardiovascular Disease and All- Cause Death: Evidence From the UK Biobank Cohort Study. J Am Heart Assoc. 2023. August 10. PMID: 37581386 PMCID: PMC10492942 Free PMC article https://www.ahajournals.org/doi/10.1161/JAHA.123.030105
  46. NEJM Knowledge+