h revised edition. new york, ny: irvington publishers; 1998. % of women experiencing an unintended pregnancy within the first year of use % of women continuing use at one year among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. method (1) typical use among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. (2) perfect use among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. (3) (4) chance the percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. among such populations, about 89% become pregnant within one year. this estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether. 85 85 spermicides foams, creams, gels, vaginal suppositories, and vaginal film. 26 6 40 periodic abstinence 25 63 calendar 9 ovulation method 3 sympto-thermal cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. 2 post-ovulation 1 cap with spermicidal cream or jelly. parous women 40 26 42 nulliparous women 20 9 56 sponge parous women 40 20 42 nulliparous women 20 9 56 diaphragm 20 6 56 withdrawal 19 4 condom without spermicides. female (reality) 21 5 56 male 14 3 61 pill 5 71 progestin only 0.5 combined 0.1 iud progesterone t 2 1.5 81 copper t380a 0.8 0.6 78 lng 20 0.1 0.1 81 depo-provera ® 0.3 0.3 70 levonorgestrel implants (norplant ® ) 0.05 0.05 88 female sterilization 0.5 0.5 100 male sterilization 0.15 0.1 100 emergency contraceptive pills: the fda has concluded that certain combined oral contraceptives containing ethinyl estradiol and norgestrel or levonorgestrel are safe and effective for use as postcoital emergency contraception. treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%. the treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. the fda has declared the following dosage regimens of oral contraceptives to be safe and effective for emergency contraception: for tablets containing 50 mcg of ethinyl estradiol and 500 mcg of norgestrel 1 dose is 2 tablets; for tablets containing 20 mcg of ethinyl estradiol and 100 mcg of levonorgestrel 1 dose is 5 tablets; for tablets containing 30 mcg of ethinyl estradiol and 150 mcg of levonorgestrel 1 dose is 4 tablets. lactation amenorrhea method: lam is a highly effective, temporary method of contraception. however, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches 6 months of age. in a clinical trial with aviane (levonorgestrel and ethinyl estradiol tablets usp), 1,477 subjects had 7,720 cycles of use and a total of 5 pregnancies were reported. this represents an overall pregnancy rate of 0.84 per 100 woman-years. this rate includes patients who did not take the drug correctly. one or more pills were missed during 1,479 (18.8%) of the 7,870 cycles; thus all tablets were taken during 6,391 (81.2%) of the 7,870 cycles. of the total 7,870 cycles, a total of 150 cycles were excluded from the calculation of the pearl index due to the use of backup contraception and/or missing 3 or more consecutive pills.

on the first sunday after the onset of menstruation. if menstruation begins on a sunday, the first tablet (orange) is taken that day. one orange tablet should be taken daily for 21 consecutive days, followed by one light-green inert tablet daily for 7 consecutive days. withdrawal bleeding should usually occur within 3 days following discontinuation of orange tablets and may not have finished before the next pack is started. during the first cycle, contraceptive reliance should not be placed on aviane - 28 until an orange tablet has been taken daily for 7 consecutive days, and a nonhormonal backup method of birth control should be used during those 7 days. day 1 start during the first cycle of medication, the patient is instructed to begin taking aviane - 28 during the first 24 hours of her period (day one of her menstrual cycle). one orange tablet should be taken daily for 21 consecutive days, followed by one light-green inert tablet daily for 7 consecutive days. withdrawal bleeding should usually occur within 3 days following discontinuation of orange tablets and may not have finished before the next pack is started. if medication is begun on day one of the menstrual cycle, no backup contraception is necessary. if aviane - 28 tablets are started later than day one of the first menstrual cycle or postpartum, contraceptive reliance should not be placed on aviane - 28 tablets until after the first 7 consecutive days of administration, and a nonhormonal backup method of birth control should be used during those 7 days. after the first cycle of use the patient begins her next and all subsequent courses of tablets on the day after taking her last light-green tablet. she should follow the same dosing schedule: 21 days on orange tablets followed by 7 days on light-green tablets. if in any cycle the patient starts tablets later than the proper day, she should protect herself against pregnancy by using a nonhormonal backup method of birth control until she has taken an orange tablet daily for 7 consecutive days. switching from another hormonal method of contraception when the patient is switching from a 21 day regimen of tablets, she should wait 7 days after her last tablet before she starts aviane. she will probably experience withdrawal bleeding during that week. she should be sure that no more than 7 days pass after her previous 21 day regimen. when the patient is switching from a 28 day regimen of tablets, she should start her first pack of aviane on the day after her last tablet. she should not wait any days between packs. the patient may switch any day from a progestin-only pill and should begin aviane the next day. if switching from an implant or injection, the patient should start aviane on the day of implant removal or, if using an injection, the day the next injection would be due. in switching from a progestin-only pill, injection, or implant, the patient should be advised to use a nonhormonal backup method of birth control for the first 7 days of tablet taking. if spotting or breakthrough bleeding occurs if spotting or breakthrough bleeding occur, the patient is instructed to continue on the same regimen. this type of bleeding is usually transient and without significance; however, if the bleeding is persistent or prolonged, the patient is advised to consult her physician. risk of pregnancy if tablets are missed while there is little likelihood of ovulation occurring if only one or two orange tablets are missed, the possibility of ovulation increases with each successive day that scheduled orange tablets are missed. although the occurrence of pregnancy is unlikely if aviane is taken according to directions, if withdrawal bleeding does not occur, the possibility of pregnancy must be considered. if the patient has not adhered to the prescribed schedule (missed one or more tablets or started taking them on a day later than she should have), the probability of pregnancy should be considered at the time of the first missed period and appropriate diagnostic measures taken. if the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out. the risk of pregnancy increases with each active (orange) tablet missed. for additional patient instructions regarding missed tablets, see the what to do if you miss pills section in the detailed patient labeling below. use after pregnancy, abortion or miscarriage aviane may be initiated no earlier than day 28 postpartum in the nonlactating mother or after a second trimester abortion due to the increased risk for thromboembolism (see contraindications , warnings , and precautions concerning thromboembolic disease). the patient should be advised to use a nonhormonal backup method for the first 7 days of tablet taking. aviane may be initiated immediately after a first trimester abortion or miscarriage. if the patient starts aviane immediately, backup contraception is not needed.

ere reactions with respiratory and circulatory symptoms 4. breast changes: tenderness, pain, enlargement, secretion 5. budd-chiari syndrome 6. cervical erosion and secretion, change in 7. cholestatic jaundice 8. chorea, exacerbation of 9. colitis 10. contact lenses, intolerance to 11. corneal curvature (steepening), change in 12. dizziness 13. edema/fluid retention 14. erythema multiforme 15. erythema nodosum 16. gastrointestinal symptoms (such as abdominal pain, cramps, and bloating) 17. hirsutism 18. infertility after discontinuation of treatment, temporary 19. lactation, diminution in, when given immediately postpartum 20. libido, change in 21. melasma/chloasma which may persist 22. menstrual flow, change in 23. mood changes, including depression 24. nausea 25. nervousness 26. pancreatitis 27. porphyria, exacerbation of 28. rash (allergic) 29. scalp hair, loss of 30. serum folate levels, decrease in 31. spotting 32. systemic lupus erythematosus, exacerbation of 33. unscheduled bleeding 34. vaginitis, including candidiasis 35. varicose veins, aggravation of 36. vomiting 37. weight or appetite (increase or decrease), change in the following adverse reactions have been reported in users of oral contraceptives: 1. cataracts 2. cystitis-like syndrome 3. dysmenorrhea 4. hemolytic uremic syndrome 5. hemorrhagic eruption 6. optic neuritis, which may lead to partial or complete loss of vision 7. premenstrual syndrome 8. renal function, impaired

gestrel are 2.8 ± 0.9 ng/ml (mean ± sd) at 1.6 ± 0.9 hours. at steady state, attained from day 19 onwards, maximum levonorgestrel concentrations of 6 ± 2.7 ng/ml are reached at 1.5 ± 0.5 hours after the daily dose. the minimum serum levels of levonorgestrel at steady state are 1.9 ± 1 ng/ml. observed levonorgestrel concentrations increased from day 1 (single dose) to days 6 and 21 (multiple doses) by 34% and 96%, respectively ( figure i ). unbound levonorgestrel concentrations increased from day 1 to days 6 and 21 by 25% and 83%, respectively. the kinetics of total levonorgestrel are nonlinear due to an increase in binding of levonorgestrel to sex hormone binding globulin (shbg), which is attributed to increased shbg levels that are induced by the daily administration of ethinyl estradiol. following a single dose, maximum serum concentrations of ethinyl estradiol of 62 ± 21 pg/ml are reached at 1.5 ± 0.5 hours. at steady state, attained from at least day 6 onwards, maximum concentrations of ethinyl estradiol were 77 ± 30 pg/ml and were reached at 1.3 ± 0.7 hours after the daily dose. the minimum serum levels of ethinyl estradiol at steady state are 10.5 ± 5.1 pg/ml. ethinyl estradiol concentrations did not increase from days 1 to 6, but did increase by 19% from days 1 to 21 ( figure i ). figure i: mean (se) levonorgestrel and ethinyl estradiol serum concentrations in 22 subjects receiving 100 mcg levonorgestrel and 20 mcg ethinyl estradiol table i provides a summary of levonorgestrel and ethinyl estradiol pharmacokinetic parameters. table i: mean (sd) pharmacokinetic parameters of aviane over a 21 day dosing period levonorgestrel c max t max auc cl/f vλz/f shbg day ng/ml h ng•h/ml ml/h/kg l/kg nmol/l 1 2.75 (0.88) 1.6 (0.9) 35.2 (12.8) 53.7 (20.8) 2.66 (1.09) 57 (18) 6 4.52 (1.79) 1.5 (0.7) 46 (18.8) 40.8 (14.5) 2.05 (0.86) 81 (25) 21 6 (2.65) 1.5 (0.5) 68.3 (32.5) 28.4 (10.3) 1.43 (0.62) 93 (40) unbound levonorgestrel pg/ml h pg•h/ml l/h/kg l/kg fu% 1 51.2 (12.9) 1.6 (0.9) 654 (201) 2.79 (0.97) 135.9 (41.8) 1.92 (0.3) 6 77.9 (22) 1.5 (0.7) 794 (240) 2.24 (0.59) 112.4 (40.5) 1.80 (0.24) 21 103.6 (36.9) 1.5 (0.5) 1177 (452) 1.57 (0.49) 78.6 (29.7) 1.78 (0.19) ethinyl estradiol pg/ml h pg•h/ml ml/h/kg l/kg 1 62 (20.5) 1.5 (0.5) 653 (227) 567 (204) 14.3 (3.7) 6 76.7 (29.9) 1.3 (0.7) 604 (231) 610 (196) 15.5 (4) 21 82.3 (33.2) 1.4 (0.6) 776 (308) 486 (179) 12.4 (4.1) figure 1 distribution levonorgestrel in serum is primarily bound to shbg. ethinyl estradiol is about 97% bound to plasma albumin. ethinyl estradiol does not bind to shbg, but induces shbg synthesis. metabolism levonorgestrel the most important metabolic pathway occurs in the reduction of the Δ4-3-oxo group and hydroxylation at positions 2α, 1β, and 16β, followed by conjugation. most of the metabolites that circulate in the blood are sulfates of 3α,5β-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. some of the parent levonorgestrel also circulates as 17β-sulfate. metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users. ethinyl estradiol cytochrome p450 enzymes (cyp3a4) in the liver are responsible for the 2-hydroxylation that is the major oxidative reaction. the 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal excretion. levels of cytochrome p450 (cyp3a) vary widely among individuals and can explain the variation in rates of ethinyl estradiol 2-hydroxylation. ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates, and undergoes enterohepatic circulation. excretion the elimination half-life for levonorgestrel is approximately 36 ± 13 hours at steady state. levonorgestrel and its metabolites are primarily excreted in the urine (40% to 68%) and about 16% to 48% are excreted in feces. the elimination half-life of ethinyl estradiol is 18 ± 4.7 hours at steady state. special populations race based on the pharmacokinetic study with aviane, there are no apparent differences in pharmacokinetic parameters among women of different races. hepatic insufficiency no formal studies have evaluated the effect of hepatic disease on the disposition of aviane. however, steroid hormones may be poorly metabolized in patients with impaired liver function. renal insufficiency no formal studies have evaluated the effect of renal disease on the disposition of aviane. drug-drug interactions see precautions section - drug interactions

ay 1 (single dose) to days 6 and 21 (multiple doses) by 34% and 96%, respectively ( figure i ). unbound levonorgestrel concentrations increased from day 1 to days 6 and 21 by 25% and 83%, respectively. the kinetics of total levonorgestrel are nonlinear due to an increase in binding of levonorgestrel to sex hormone binding globulin (shbg), which is attributed to increased shbg levels that are induced by the daily administration of ethinyl estradiol. following a single dose, maximum serum concentrations of ethinyl estradiol of 62 ± 21 pg/ml are reached at 1.5 ± 0.5 hours. at steady state, attained from at least day 6 onwards, maximum concentrations of ethinyl estradiol were 77 ± 30 pg/ml and were reached at 1.3 ± 0.7 hours after the daily dose. the minimum serum levels of ethinyl estradiol at steady state are 10.5 ± 5.1 pg/ml. ethinyl estradiol concentrations did not increase from days 1 to 6, but did increase by 19% from days 1 to 21 ( figure i ). figure i: mean (se) levonorgestrel and ethinyl estradiol serum concentrations in 22 subjects receiving 100 mcg levonorgestrel and 20 mcg ethinyl estradiol table i provides a summary of levonorgestrel and ethinyl estradiol pharmacokinetic parameters. table i: mean (sd) pharmacokinetic parameters of aviane over a 21 day dosing period levonorgestrel c max t max auc cl/f vλz/f shbg day ng/ml h ng•h/ml ml/h/kg l/kg nmol/l 1 2.75 (0.88) 1.6 (0.9) 35.2 (12.8) 53.7 (20.8) 2.66 (1.09) 57 (18) 6 4.52 (1.79) 1.5 (0.7) 46 (18.8) 40.8 (14.5) 2.05 (0.86) 81 (25) 21 6 (2.65) 1.5 (0.5) 68.3 (32.5) 28.4 (10.3) 1.43 (0.62) 93 (40) unbound levonorgestrel pg/ml h pg•h/ml l/h/kg l/kg fu% 1 51.2 (12.9) 1.6 (0.9) 654 (201) 2.79 (0.97) 135.9 (41.8) 1.92 (0.3) 6 77.9 (22) 1.5 (0.7) 794 (240) 2.24 (0.59) 112.4 (40.5) 1.80 (0.24) 21 103.6 (36.9) 1.5 (0.5) 1177 (452) 1.57 (0.49) 78.6 (29.7) 1.78 (0.19) ethinyl estradiol pg/ml h pg•h/ml ml/h/kg l/kg 1 62 (20.5) 1.5 (0.5) 653 (227) 567 (204) 14.3 (3.7) 6 76.7 (29.9) 1.3 (0.7) 604 (231) 610 (196) 15.5 (4) 21 82.3 (33.2) 1.4 (0.6) 776 (308) 486 (179) 12.4 (4.1) figure 1 distribution levonorgestrel in serum is primarily bound to shbg. ethinyl estradiol is about 97% bound to plasma albumin. ethinyl estradiol does not bind to shbg, but induces shbg synthesis. metabolism levonorgestrel the most important metabolic pathway occurs in the reduction of the Δ4-3-oxo group and hydroxylation at positions 2α, 1β, and 16β, followed by conjugation. most of the metabolites that circulate in the blood are sulfates of 3α,5β-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. some of the parent levonorgestrel also circulates as 17β-sulfate. metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users. ethinyl estradiol cytochrome p450 enzymes (cyp3a4) in the liver are responsible for the 2-hydroxylation that is the major oxidative reaction. the 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal excretion. levels of cytochrome p450 (cyp3a) vary widely among individuals and can explain the variation in rates of ethinyl estradiol 2-hydroxylation. ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates, and undergoes enterohepatic circulation. excretion the elimination half-life for levonorgestrel is approximately 36 ± 13 hours at steady state. levonorgestrel and its metabolites are primarily excreted in the urine (40% to 68%) and about 16% to 48% are excreted in feces. the elimination half-life of ethinyl estradiol is 18 ± 4.7 hours at steady state.