ear among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. method 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. 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. (1) (2) (3) (4) emergency contraceptive pills: 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 food and drug administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: ovral (1 dose is 2 white pills), aleese (1 dose is 5 pink pills), nordette or levlen (1 dose is 2 light-orange pills), lo/ovral (1 dose is 4 white pills), triphasil or tri-levlen (1 dose is 4 yellow pills). lactational 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 six months of age. source: trussell j. contraceptive efficacy table from hatcher r.a., trussell j, stewart f, cates w, stewart gk, kowal d, guest f, in contraceptive technology: seventeenth revised edition. new york, ny: irvington publishers, 1998. 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 withdrawal 19 4 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 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 2.0 1.5 81 copper t 380a 0.8 0.6 78 lng 20 0.1 0.1 81 depo-provera 0.3 0.3 70 norplant and norplant-2 0.05 0.05 88 female sterilization 0.5 0.5 100 male sterilization 0.15 0.10 100

rt is principally based on studies carried out in patients who used oral contraceptives with higher formulations of both estrogens and progestogens than those in common use today. 6–11 the effect of long-term use of the oral contraceptives with lower formulations 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 a disease. relative risk, the ratio of the incidence of a disease among oral contraceptive users to that among non-users, cannot be assessed directly from case control studies, but the odds ratio obtained is a measure of relative risk. the relative risk does not provide information on the actual clinical occurrence of a disease. cohort studies provide not only a measure of the relative risk but a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and non-users. the attributable risk does provide information about the actual occurrence of a disease in the population (adapted from ref. 12 and 13 with the author's permission). 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. 2–5, 13 the relative risk of heart attack for current oral contraceptive users has been estimated to be 2 to 6. 2, 14–19 the risk is very low under the age of 30. however, there is the possibility of a risk of cardiovascular disease even in very young women who take oral contraceptives. smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older, with smoking accounting for the majority of excess cases. 20 mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and non-smokers over the age of 40 among women who use oral contraceptives (see table ii ). 16 table ii: circulatory disease mortality rates per 100,000 woman years by age, smoking status and oral contraceptive use adapted from p.m. layde and v. beral, table v 16 oral contraceptives may compound the effects of well-known risk factors such as hypertension, diabetes, hyperlipidemias, hypercholesterolemia, age and obesity. 3, 13, 21 in particular, some progestogens are known to decrease hdl cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. 21–25 oral contraceptives have been shown to increase blood pressure among users (see warnings, section 9 ). 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. table ii b. thromboembolism an increased risk of 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. 12,13,26–31 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. 32 the risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped. 12 a 2- to 6-fold increase in relative risk of post-operative 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. 83 if feasible, oral contraceptives should be discontinued at least 4 weeks prior to and for 2 weeks after elective surgery and during and following prolonged immobilization. since the immediate postpartum period also is associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than 4 to 6 weeks after delivery in women who elect not to breast feed. 33 c. cerebrovascular diseases an increase in both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes) has been shown in users of oral contraceptives. in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. hypertension was found to be a risk factor for both users and non-users for both types of strokes while smoking interacted to increase the risk for hemorrhagic strokes. 34 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. 35 the relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers 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. 35 the attributable risk also is greater in women in their mid-thirties or older and among smokers. 13 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. 36–38 a decline in serum high density lipoproteins (hdl) has been reported with many progestational agents. 22–24 a decline in serum high density lipoproteins has been associated with an increased incidence of ischemic heart disease. 39 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 progestogens used in the contraceptives. the amount of both hormones should be considered in the choice of an oral contraceptive. 37 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 that produces satisfactory results for the individual. products containing 50 mcg estrogen should be used only when medically indicated. e. persistence of risk of vascular disease there are three studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. 17, 34, 40 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 40–49 years who had used oral contraceptives for 5 or more years, but this increased risk was not demonstrated in other age groups. 17 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. 40 there is a significantly increased relative risk of subarachnoid hemorrhage after termination of use of oral contraceptives. 34 however, these studies were performed with oral contraceptive formulations containing 50 mcg or higher of estrogen. products containing 50 mcg estrogen should be used only when medically indicated. 2. estimates of mortality from contraceptive use one study gathered data from a variety of sources which have estimated the mortality rates associated with different methods of contraception at different ages (see table iii ). 41 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 low and below 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 1970s—but not reported in the u.s. until 1983. 16, 41 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, 78, 79 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 non-smoking 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 non-smoking 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. 80 table iii: estimated annual number of birth-related or method-related deaths associated with control of fertility per 100,000 non-sterile women, by fertility control method according to age method of control and outcome 15-19 20-24 25-29 30-34 35-39 40-44 estimates adapted from h.w. ory, table 3 41 no fertility 7.0 7.4 9.1 14.8 25.7 28.2 control methods deaths are birth-related oral contraceptives 0.3 0.5 0.9 1.9 13.8 31.6 non-smoker deaths are method-related oral contraceptives 2.2 3.4 6.6 13.5 51.1 117.2 smoker 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 leena 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 in some populations of women. 50-53 however, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. in spite of many studies of the relationship between oral contraceptive use and breast or cervical cancers, a cause-and-effect relationship has not been established. 4. hepatic neoplasia benign hepatic adenomas are associated with oral contraceptive use although the incidence of benign tumors is rare in the united states. indirect calculations have estimated the attributable risk to be in the range of 3.3 cases per 100,000 for users, a risk that increases after 4 or more years of use. 54 rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage. 55–56 studies in the united states and britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive users. 57–59 however, these cancers are rare in the u.s. and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than 1 per 1,000,000 users. 5. 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 leena prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [ see contraindications ]. leena can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen. 6. ocular lesions there have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. 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. 7. oral contraceptive use before or during early pregnancy extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. 60–62 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. 60,61,63,64 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 2 consecutive periods, pregnancy should be ruled out before continuing oral contraceptive use. if the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the first missed period. oral contraceptive use should be discontinued if pregnancy is confirmed. 8. gallbladder disease earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. 65–66 more recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal. 67 the recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens. 68 9. carbohydrate and lipid metabolic effects oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users. 25 oral contraceptives containing greater than 75 mcg of estrogen cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance. 70 progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. 25,71 however, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. 69 because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives. some women may develop persistent hypertriglyceridemia while on the pill. 72 as discussed earlier (see warnings, sections 1a. and 1d. ), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users. 23 10. 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. 73,84 data from the royal college of general practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing concentrations 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 elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs oral contraceptives should be discontinued. 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. 73–75 11. headache the onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent or severe requires discontinuation of oral contraceptives and evaluation of the cause. 12. bleeding irregularities breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first 3 months of use. non-hormonal 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, especially when such a condition was pre-existent.

oc" are females with current or past coc use; "never coc use" are females that never used cocs. an increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see warnings section): thrombophlebitis arterial thromboembolism pulmonary embolism myocardial infarction cerebral hemorrhage cerebral thrombosis hypertension gallbladder disease hepatic adenomas, carcinomas or benign liver tumors there is evidence of an association between the following conditions and the use of oral contraceptives, although additional confirmatory studies are needed: mesenteric thrombosis retinal thrombosis the following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related: nausea vomiting gastrointestinal symptoms (such as abdominal cramps and bloating) breakthrough bleeding spotting change in menstrual flow amenorrhea temporary infertility after discontinuation of treatment edema melasma which may persist breast changes: tenderness, enlargement, secretion change in weight (increase or decrease) change in cervical erosion and secretion diminution in lactation when given immediately postpartum cholestatic jaundice migraine rash (allergic) mental depression reduced tolerance to carbohydrates vaginal candidiasis change in corneal curvature (steepening) intolerance to contact lenses the following adverse reactions have been reported in users of oral contraceptives and the association has been neither confirmed nor refuted: pre-menstrual syndrome cataracts changes in appetite cystitis-like syndrome headache nervousness dizziness hirsutism loss of scalp hair erythema multiforme erythema nodosum hemorrhagic eruption vaginitis porphyria impaired renal function hemolytic uremic syndrome budd-chiari syndrome acne changes in libido colitis figure 1

es increase significantly if you: smoke have high blood pressure, diabetes or high cholesterol have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice or malignant or benign liver tumors you should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding. cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. this risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. women who use oral contraceptives are strongly advised not to 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 3 months of use. the serious side effects of the pill occur very infrequently, especially if you are in good health and are young. 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) or lungs (pulmonary embolism), stoppage or rupture of a blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack or angina pectoris), eye or other organs of the body. as mentioned above, smoking increases the risk of heart attacks and strokes and subsequent serious medical consequences. 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 doctor or health care provider if you notice any unusual physical disturbances while taking the pill. in addition, drugs such as rifampin, as well as some anti-convulsants and some antibiotics, 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 non-contraceptive health 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 a good medical practice 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 the pill see full text of how to take the pill which is printed in full in the detailed patient labeling. call your doctor for medical advice about side effects. you may report side effects to mayne pharma at 1-844-825-8500 or to fda at 1-800-fda-1088. distributed by: mayne pharma greenville, nc 27834 manufactured by: patheon, inc. mississauga, ontario l5n 7k9 canada revised: april 2022 2000014496