inconsistent results. several of the anti-hiv protease inhibitors have been studied with co-administration of oral combination hormonal contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. the safety and efficacy of oral contraceptive products may be affected with coadministration of anti-hiv protease inhibitors. healthcare providers should refer to the label of the individual anti-hiv protease inhibitors for further drug-drug interaction information. herbal products containing st. john’s wort ( hypericum perforatum ) may induce hepatic enzymes (cytochrome p 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. this may also result in breakthrough bleeding. increase in plasma levels associated with co-administered drugs co-administration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increases auc values for ethinyl estradiol by approximately 20%. ascorbic acid and acetaminophen increase the bioavailability of ethinyl estradiol since these drugs act as competitive inhibitors for sulfation of ethinyl estradiol in the gastrointestinal wall, a known pathway of elimination for ethinyl estradiol. cyp 3a4 inhibitors such as indinavir, itraconazole, ketoconazole, fluconazole, and troleandomycin may increase plasma hormone levels. troleandomycin may also increase the risk of intrahepatic cholestasis during coadministration with combination oral contraceptives. changes in plasma levels of co-administered drugs combination hormonal contraceptives containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. increased plasma concentrations of cyclosporine, prednisolone and other corticosteroids, and theophylline have been reported with concomitant administration of oral contraceptives. decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid, due to induction of conjugation (particularly glucuronidation), have been noted when these drugs were administered with oral contraceptives. the prescribing information of concomitant medications should be consulted to identify potential interactions. concomitant use with hcv combination therapy – liver enzyme elevation do not co-administer afirmelle with hcv drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for alt elevations (see warnings, risk of liver enzyme elevations with concomitant hepatitis c treatment ).

4 condom 8 female (reality) 21 5 56 male 14 3 61 pill 5 71 progestin only 0.5 combined 0.1 iud progesterone t 2.0 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 0.10 100 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%. 9 lactation amenorrhea method: lam is a highly effective, temporary method of contraception. 10 source: trussell j. contraceptive efficacy. in: hatcher ra, trussell j, stewart f, cates w, stewart gk, kowel d, guest f. contraceptive technology: seventeenth revised edition. new york ny: irvington publishers; 1998. 1. 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. 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. among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. 4. 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. 5. foams, creams, gels, vaginal suppositories, and vaginal film. 6. cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. 7. with spermicidal cream or jelly. 8. without spermicides. 9. 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. 10. 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 levonorgestrel and ethinyl estradiol tablets, 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.

, obesity, diabetes, and surgery or trauma with increased risk of thrombosis (see contraindications ). practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks. the information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher doses of estrogens and progestogens than those in common use today. the effect of long-term use of the oral contraceptives with lower doses of both estrogens and progestogens remains to be determined. throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. case control studies provide a measure of the relative risk of disease, namely, a ratio of the incidence of a disease among oral-contraceptive users to that among nonusers. the relative risk does not provide information on the actual clinical occurrence of a disease. cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral-contraceptive users and nonusers. the attributable risk does provide information about the actual occurrence of a disease in the population. for further information, the reader is referred to a text on epidemiological methods. 1. thromboembolic disorders and other vascular problems a. myocardial infarction an increased risk of myocardial infarction has been attributed to oral-contraceptive use. this risk is primarily in smokers or women with other underlying risk factors for coronary-artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. the relative risk of heart attack for current oral-contraceptive users has been estimated to be two to six. the risk is very low under the age of 30. smoking in combination with oral-contraceptive use has been shown to contribute substantially to the incidence of myocardial infarction in women in their mid-thirties or older with smoking accounting for the majority of excess cases. mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 (figure ii) among women who use oral contraceptives. figure ii. (adapted from p.m. layde and v. beral, lancet, 1:541-546, 1981.) oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age, and obesity. in particular, some progestogens are known to decrease hdl cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. oral contraceptives have been shown to increase blood pressure among users (see section 9 in warnings ). similar effects on risk factors have been associated with an increased risk of heart disease. oral contraceptives must be used with caution in women with cardiovascular disease risk factors. b. venous thrombosis and thromboembolism an increased risk of venous thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. case control studies have found the relative risk of users compared to non-users to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep-vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. the approximate incidence of deep-vein thrombosis and pulmonary embolism in users of low dose (less than 50 mcg ethinyl estradiol) combination oral contraceptives is up to 4 per 10,000 woman-years compared to 0.5 to 3 per 10,000 woman-years for non-users. however, the incidence is less than that associated with pregnancy (6 per 10,000 woman-years). the excess risk is highest during the first year a woman ever uses a combined oral contraceptive. venous thromboembolism may be fatal. the risk of thromboembolic disease due to oral contraceptives is not related to length of use and gradually disappears after pill use is stopped. a two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives. the relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. if feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breast-feed or after a midtrimester pregnancy termination. c. cerebrovascular diseases oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (greater than 35 years), hypertensive women who also smoke. hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes. in a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension. the relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension. the attributable risk is also greater in older women. oral contraceptives also increase the risk for stroke in women with other underlying risk factors such as certain inherited or acquired thrombophilias. women with migraine (particularly migraine/headaches with focal neurological symptoms, see contraindications ) who take combination oral contraceptives may be at an increased risk of stroke. d. dose-related risk of vascular disease from oral contraceptives a positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease. a decline in serum high-density lipoproteins (hdl) has been reported with many progestational agents. a decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. because estrogens increase hdl cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogen used in the contraceptive. the amount of both hormones should be considered in the choice of an oral contraceptive. minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. for any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. new acceptors of oral contraceptive agents should be started on preparations containing the lowest estrogen content which is judged appropriate for the individual patient. e. persistence of risk of vascular disease there are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. in a study in the united states, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40 to 49 years who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups. in another study in great britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small. however, both studies were performed with oral contraceptive formulations containing 50 mcg or higher of estrogens. circulatory disease mortality rates per 100,000 woman years by age, smoking status and oral-contraceptive use 2. estimates of mortality from contraceptive use one study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (table iii). these estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. each method of contraception has its specific benefits and risks. the study concluded that with the exception of oral-contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is less than that associated with childbirth. the observation of a possible increase in risk of mortality with age for oral-contraceptive users is based on data gathered in the 1970’s — but not reported until 1983. however, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral-contraceptive use to women who do not have the various risk factors listed in this labeling. because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed, the fertility and maternal health drugs advisory committee was asked to review the topic in 1989. the committee concluded that although cardiovascular disease risks may be increased with oral-contraceptive use after age 40 in healthy nonsmoking women (even with the newer low-dose formulations), there are greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception. therefore, the committee recommended that the benefits of oral-contraceptive use by healthy nonsmoking women over 40 may outweigh the possible risks. of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective. table iii: annual number of birth-related or method-related deaths associated with control of fertility per 100,000 nonsterile women, by fertility-control method and according to age * deaths are birth related ** deaths are method related adapted from h.w. ory, family planning perspectives, 15 :57-63, 1983. method of control and outcome 15 to 19 20 to 24 25 to 29 30 to 34 35 to 39 40 to 44 no fertility-control methods * 7.0 7.4 9.1 14.8 25.7 28.2 oral contraceptives nonsmoker ** 0.3 0.5 0.9 1.9 13.8 31.6 oral contraceptives smoker ** 2.2 3.4 6.6 13.5 51.1 117.2 iud ** 0.8 0.8 1.0 1.0 1.4 1.4 condom * 1.1 1.6 0.7 0.2 0.3 0.4 diaphragm/spermicide * 1.9 1.2 1.2 1.3 2.2 2.8 periodic abstinence * 2.5 1.6 1.6 1.7 2.9 3.6 3. malignant neoplasms breast cancer afirmelle is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see contraindications]. epidemiology studies have not found a consistent association between use of combined oral contraceptives (cocs) and breast cancer risk. studies do not show an association between ever (current or past) use of cocs and risk of breast cancer. however, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of coc use [see postmarketing experience ]. cervical cancer some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia or invasive cervical cancer in some populations of women. however, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. 4. hepatic neoplasia benign hepatic adenomas are associated with oral-contraceptive use, although the incidence of these benign tumors is rare in the united states. indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use. rupture of rare, benign, hepatic adenomas may cause death through intra abdominal hemorrhage. studies from britain have shown an increased risk of developing hepatocellular carcinoma in long-term (greater than 8 years) oral-contraceptive users. however, these cancers are extremely rare in the u.s. and the attributable risk (the excess incidence) of liver cancers in oral-contraceptive users approaches less than one per million users. risk of liver enzyme elevations with concomitant hepatitis c treatment during clinical trials with the hepatitis c combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, alt elevations greater than 5 times the upper limit of normal (uln), including some cases greater than 20 times the uln, were significantly more frequent in women using ethinyl estradiol-containing medications such as cocs. discontinue afirmelle prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (see contraindications ). afirmelle can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen. 5. ocular lesions there have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives that may lead to partial or complete loss of vision. oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. appropriate diagnostic and therapeutic measures should be undertaken immediately. 6. oral-contraceptive use before or during early pregnancy extensive epidemiological studies have revealed no increased risk of birth defects in infants born to women who have used oral contraceptives prior to pregnancy. studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy (see contraindications section). the administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion. it is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out. if the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period. oral-contraceptive use should be discontinued if pregnancy is confirmed. 7. gallbladder disease combination oral contraceptives may worsen existing gallbladder disease and may accelerate the development of this disease in previously asymptomatic women. earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. more recent studies, however, have shown that the relative risk of developing gallbladder disease among oral-contraceptive users may be minimal. the recent findings of minimal risk may be related to the use of oral-contraceptive formulations containing lower hormonal doses of estrogens and progestogens. 8. carbohydrate and lipid metabolic effects oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users. oral contraceptives containing greater than 75 mcg of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance. progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. however, in the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives. a small proportion of women will have persistent hypertriglyceridemia while on the pill. as discussed earlier (see warnings, 1a . and 1d .; precautions, 3 .), changes in serum triglycerides and lipoprotein levels have been reported in oral-contraceptive users. 9. elevated blood pressure an increase in blood pressure has been reported in women taking oral contraceptives and this increase is more likely in older oral-contraceptive users and with continued use. data from the royal college of general practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing quantities of progestogens. women with a history of hypertension or hypertension-related diseases, or renal disease should be encouraged to use another method of contraception. if women with hypertension elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued (see contraindications section). for most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension among ever- and never-users. 10. headache the onset or exacerbation of migraine or development of headache with a new pattern that is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause. (see warnings, 1c . and contrindications .) 11. bleeding irregularities breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. the type and dose of progestogen may be important. if bleeding persists or recurs, nonhormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. if pathology has been excluded, time or a change to another formulation may solve the problem. in the event of amenorrhea, pregnancy should be ruled out. some women may encounter post-pill amenorrhea or oligomenorrhea (possibly with anovulation), especially when such a condition was preexistent. 12. ectopic pregnancy ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

first sunday after the onset of menstruation. if menstruation begins on a sunday, the first tablet (white) is taken that day. one white tablet should be taken daily for 21 consecutive days, followed by one green inert tablet daily for 7 consecutive days. withdrawal bleeding should usually occur within 3 days following discontinuation of white tablets and may not have finished before the next pack is started. during the first cycle, contraceptive reliance should not be placed on afirmelle until a white tablet has been taken daily for 7 consecutive days, and a nonhormonal back-up 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 afirmelle during the first 24 hours of her period (day one of her menstrual cycle). one white tablet should be taken daily for 21 consecutive days, followed by one green inert tablet daily for 7 consecutive days. withdrawal bleeding should usually occur within 3 days following discontinuation of white tablets and may not have finished before the next pack is started. if medication is begun on day one of the menstrual cycle, no back-up contraception is necessary. if afirmelle tablets are started later than day one of the first menstrual cycle or postpartum, contraceptive reliance should not be placed on afirmelle tablets until after the first 7 consecutive days of administration, and a nonhormonal back-up 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 green tablet. she should follow the same dosing schedule: 21 days on white tablets followed by 7 days on 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 back-up method of birth control until she has taken a white 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 afirmelle. 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 afirmelle 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 afirmelle the next day. if switching from an implant or injection, the patient should start afirmelle 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 back-up 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 white tablets are missed, the possibility of ovulation increases with each successive day that scheduled white tablets are missed. although the occurrence of pregnancy is unlikely if afirmelle 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 (white) 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 afirmelle 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 back-up method for the first 7 days of tablet taking. afirmelle may be initiated immediately after a first trimester abortion or miscarriage. if the patient starts afirmelle immediately, back-up contraception is not needed.

ions with respiratory and circulatory symptoms. breast changes: tenderness, pain, enlargement, secretion budd-chiari syndrome cervical erosion and secretion, change in cholestatic jaundice chorea, exacerbation of colitis contact lenses, intolerance to corneal curvature (steepening), change in dizziness edema/fluid retention erythema multiforme erythema nodosum gastrointestinal symptoms (such as abdominal pain, cramps, and bloating) hirsutism infertility after discontinuation of treatment, temporary lactation, diminution in, when given immediately postpartum libido, change in melasma/chloasma which may persist menstrual flow, change in mood changes, including depression nausea nervousness pancreatitis porphyria, exacerbation of rash (allergic) scalp hair, loss of serum folate levels, decrease in spotting systemic lupus erythematosus, exacerbation of unscheduled bleeding vaginitis, including candidiasis varicose veins, aggravation of vomiting weight or appetite (increase or decrease), change in the following adverse reactions have been reported in users of oral contraceptives: cataracts cystitis-like syndrome dysmenorrhea hemolytic uremic syndrome hemorrhagic eruption optic neuritis, which may lead to partial or complete loss of vision premenstrual syndrome renal function, impaired post marketing experience five studies that compared breast cancer risk between ever-users (current or past use) of cocs and never-users of cocs reported no association between ever use of cocs and breast cancer risk, with effect estimates ranging from 0.90 to 1.12 (figure iii). three studies compared breast cancer risk between current or recent coc users (<6 months since last use) and never users of cocs (figure iii). one of these studies reported no association between breast cancer risk and coc use. the other two studies found an increased relative risk of 1.19 to 1.33 with current or recent use. both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of coc use to approximately 1.4 with more than 8 to 10 years of coc use. figure iii: risk of breast cancer with combined oral contraceptive use rr = relative risk; or = odds ratio; hr = hazard ratio. “ever coc” are females with current or past coc use; “never coc use” are females that never used cocs. figure iii: risk of breast cancer with combined oral contraceptive use

inconsistent results. several of the anti-hiv protease inhibitors have been studied with co-administration of oral combination hormonal contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. the safety and efficacy of oral contraceptive products may be affected with coadministration of anti-hiv protease inhibitors. healthcare providers should refer to the label of the individual anti-hiv protease inhibitors for further drug-drug interaction information. herbal products containing st. john’s wort ( hypericum perforatum ) may induce hepatic enzymes (cytochrome p 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. this may also result in breakthrough bleeding. increase in plasma levels associated with co-administered drugs co-administration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increases auc values for ethinyl estradiol by approximately 20%. ascorbic acid and acetaminophen increase the bioavailability of ethinyl estradiol since these drugs act as competitive inhibitors for sulfation of ethinyl estradiol in the gastrointestinal wall, a known pathway of elimination for ethinyl estradiol. cyp 3a4 inhibitors such as indinavir, itraconazole, ketoconazole, fluconazole, and troleandomycin may increase plasma hormone levels. troleandomycin may also increase the risk of intrahepatic cholestasis during coadministration with combination oral contraceptives. changes in plasma levels of co-administered drugs combination hormonal contraceptives containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. increased plasma concentrations of cyclosporine, prednisolone and other corticosteroids, and theophylline have been reported with concomitant administration of oral contraceptives. decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid, due to induction of conjugation (particularly glucuronidation), have been noted when these drugs were administered with oral contraceptives. the prescribing information of concomitant medications should be consulted to identify potential interactions. concomitant use with hcv combination therapy – liver enzyme elevation do not co-administer afirmelle with hcv drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for alt elevations (see warnings, risk of liver enzyme elevations with concomitant hepatitis c treatment ).

evonorgestrel 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 6.0 ± 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 ± 1.0 ng/ml. observed levonorgestrel concentrations increased from day 1 (single dose) to days 6 and 21 (multiple doses) by 34% and 96%, respectively (figure 1). unbound levonorgestrel concentrations increased from day 1 to days 6 and 21 by 25% and 83%, respectively. the kinetics of total levonorgestrel are non-linear 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 afirmelle (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 afirmelle over a 21-day dosing period levonorgestrel day c max ng/ml t max h auc ng . h/ml cl/f ml/h/kg vλz/f l/kg shbg 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) 46.0 (18.8) 40.8 (14.5) 2.05 (0.86) 81 (25) 21 6.00 (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 (0.30) 6 77.9 (22.0) 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 62.0 (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 (4.0) 21 82.3 (33.2) 1.4 (0.6) 776 (308) 486 (179) 12.4 (4.1) 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. figure i: mean (se) levonorgestrel and ethinyl estradiol serum concentrations in 22 subjects receiving levonorgestrel and ethinyl estradiol (100 mcg levonorgestrel and 20 mcg ethinyl estradiol) special populations race based on the pharmacokinetic study with afirmelle, 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 afirmelle. 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 afirmelle. drug-drug interactions see precautions section – drug interactions

ken safely. but there are some women who are at high risk of developing certain serious diseases that can be life-threatening or may cause temporary or permanent disability or death. the risks associated with taking oral contraceptives increase significantly if you: smoke. have high blood pressure, diabetes, high cholesterol, or a tendency to form blood clots. have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice, malignant or benign liver tumors, or major surgery with prolonged immobilization. have headaches with neurological symptoms. you should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding. although cardiovascular disease risks may be increased with oral-contraceptive use after age 40 in healthy, nonsmoking women, there are also greater potential health risks associated with pregnancy in older women. cigarette smoking increases the risk of serious adverse effects on the heart and blood vessels from oral-contraceptive use. this risk increases with age and with the amount of smoking (15 or more cigarettes per day has been associated with a significantly increased risk) and is quite marked in women over 35 years of age. women who use oral contraceptives should not smoke. most side effects of the pill are not serious. the most common such effects are nausea, vomiting, bleeding between menstrual periods, weight gain, breast tenderness, and difficulty wearing contact lenses. these side effects, especially nausea and vomiting, may subside within the first three months of use. the serious side effects of the pill occur very infrequently, especially if you are in good health and do not smoke. however, you should know that the following medical conditions have been associated with or made worse by the pill: blood clots in the legs (thrombophlebitis) and lungs (pulmonary embolism), blockage or rupture of a blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack and angina pectoris) or other organs of the body. as mentioned above, smoking increases the risk of heart attacks and strokes and subsequent serious medical consequences. women with migraine also may be at increased risk of stroke with pill use. liver tumors, which may rupture and cause severe bleeding. a possible but not definite association has been found with the pill and liver cancer. however, liver cancers are extremely rare. the chance of developing liver cancer from using the pill is thus even rarer. high blood pressure, although blood pressure usually returns to normal when the pill is stopped. the symptoms associated with these serious side effects are discussed in the detailed leaflet given to you with your supply of pills. notify your health-care provider if you notice any unusual physical disturbances while taking the pill. in addition, drugs such as rifampin, as well as some anticonvulsants and some antibiotics, herbal preparations containing st. john’s wort ( hypericum perforatum ), and hiv/aids drugs may decrease oral-contraceptive effectiveness. there may be slight increases in the risk of breast cancer among current users of hormonal birth control pills with longer duration of use of 8 years or more. some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. however, this finding may be related to factors other than the use of oral contraceptives. taking the pill provides some important noncontraceptive benefits. these include less painful menstruation, less menstrual blood loss and anemia, fewer pelvic infections, and fewer cancers of the ovary and the lining of the uterus. be sure to discuss any medical condition you may have with your health-care provider. your health-care provider will take a medical and family history before prescribing oral contraceptives and will examine you. the physical examination may be delayed to another time if you request it and the health-care provider believes that it is appropriate to postpone it. you should be reexamined at least once a year while taking oral contraceptives. the detailed patient information leaflet gives you further information which you should read and discuss with your health-care provider. how to take afirmelle important points to remember before you start taking afirmelle: 1. be sure to read these directions: before you start taking afirmelle. and anytime you are not sure what to do. 2. the right way to take the pill is to take one pill every day at the same time. if you miss pills you could get pregnant. this includes starting the pack late. the more pills you miss, the more likely you are to get pregnant. see “what to do if you miss pills” below. 3. many women have spotting or light bleeding, or may feel sick to their stomach during the first 1 to 3 packs of pills. if you feel sick to your stomach, do not stop taking afirmelle. the problem will usually go away. if it doesn’t go away, check with your health-care provider. 4. missing pills can also cause spotting or light bleeding, even when you make up these missed pills. on the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 5. if you have vomiting (within 4 hours after you take your pill), you should follow the instructions for what to do if you miss pills. if you have diarrhea or if you take some medicines, including some antibiotics, your pills may not work as well. use a back-up nonhormonal method (such as condoms or spermicide) until you check with your health-care provider. 6. if you have trouble remembering to take the pill, talk to your health-care provider about how to make pill-taking easier or about using another method of birth control. 7. if you have any questions or are unsure about the information in this leaflet, call your health-care provider. before you start taking afirmelle 1. decide what time of day you want to take your pill. it is important to take it at about the same time every day. 2. look at your pill pack. the pill pack has 21 “active” white pills (with hormones) to take for 3 weeks, followed by 1 week of reminder green pills (without hormones). 3. find: 1. where on the pack to start taking pills, and 2. in what order to take the pills (follow the arrow). 4. be sure you have ready at all times: another kind of birth control (such as condoms or spermicide) to use as a back-up in case you miss pills. an extra, full pill pack. when to start the first pack of pills you have a choice of which day to start taking your first pack of pills. decide with your health-care provider which is the best day for you. pick a time of day which will be easy to remember. day 1 start 1. pick the day label strip that starts with the first day of your period. place this day label strip over the area that has the days of the week (starting with sunday) pre-printed on the tablet blister pack. note: if the first day of your period is a sunday, you can skip step#1. 2. take the first “active” white pill of the first pack during the first 24 hours of your period . 3. you will not need to use a back-up nonhormonal method of birth control, since you are starting the pill at the beginning of your period. sunday start 1. take the first “active” white pill of the first pack on the sunday after your period starts , even if you are still bleeding. if your period begins on sunday, start the pack that same day. 2. use a nonhormonal method of birth control (such as condoms or spermicide) as a backup method if you have sex anytime from the sunday you start your first pack until the next sunday (7 days). what to do during the month 1. take one pill at the same time every day until the pack is empty. do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). do not skip pills even if you do not have sex very often. 2. when you finish a pack: start the next pack on the day after your last “reminder” pill. do not wait any days between packs. if you switch from another brand of combination pills if your previous brand had 21 pills: wait 7 days to start taking afirmelle. you will probably have your period during that week. be sure that no more than 7 days pass between the 21-day pack and taking the first white afirmelle pill (“active” with hormone). if your previous brand had 28 pills: start taking the first white afirmelle pill (“active” with hormone) on the day after your last reminder pill. do not wait any days between packs. what to do if you miss pills afirmelle may not be as effective if you miss white “active” pills, and particularly if you miss the first few or the last few white “active” pills in a pack. if you miss 1 white “active” pill: 1. take it as soon as you remember. take the next pill at your regular time. this means you may take 2 pills in 1 day. 2. you could become pregnant if you have sex in the 7 days after you restart your pills. you must use a nonhormonal birth-control method (such as condoms or spermicide) as a back­-up for those 7 days. if you miss 2 white “active” pills in a row in week 1 or week 2 of your pack: 1. take 2 pills on the day you remember and 2 pills the next day. 2. then take 1 pill a day until you finish the pack. 3. you could become pregnant if you have sex in the 7 days after you restart your pills. you must use a nonhormonal birth-control method (such as condoms or spermicide) as a back­-up for those 7 days. if you miss 2 white “active” pills in a row in the 3rd week: 1. if you are a day 1 starter: throw out the rest of the pill pack and start a new pack that same day. if you are a sunday starter: keep taking 1 pill every day until sunday. on sunday, throw out the rest of the pack and start a new pack of pills that same day. 2. you may not have your period this month but this is expected however, if you miss your period 2 months in a row, call your health-care provider because you might be pregnant. 3. you could become pregnant if you have sex in the 7 days after you restart your pills. you must use a nonhormonal birth-control method (such as condoms or spermicide) as a back­-up for those 7 days. if you miss 3 or more white “active” pills in a row (during the first 3 weeks): 1. if you are a day 1 starter: throw out the rest of the pill pack and start a new pack that same day. if you are a sunday starter: keep taking 1 pill every day until sunday. on sunday, throw out the rest of the pack and start a new pack of pills that same day. 2. you may not have your period this month but this is expected. however, if you miss your period 2 months in a row, call your health-care provider because you might be pregnant. 3. you could become pregnant if you have sex in the 7 days after you restart your pills. you must use a nonhormonal birth-control method (such as condoms or spermicide) as a back­-up for those 7 days. if you forget any of the 7 green “reminder” pills in week 4: throw away the pills you missed. keep taking 1 pill each day until the pack is empty. you do not need a back-up nonhormonal birth-control method if you start your next pack on time. finally, if you are still not sure what to do about the pills you have missed use a back-up nonhormonal birth-control method anytime you have sex. keep taking one pill each day until you can reach your health-care provider. birth control after stopping the pill if you do not wish to become pregnant after stopping the pill, speak to your health-care provider about another method of birth control. figure 4 figure 5