Introvale Dailymed

Table 1Instructions for Administration of IntrovaleTM Starting COCs in women not currently using hormonal contraception (Sunday Start) Important: Consider the possibility of ovulation and conception prior to initiation of this product. Tablet Color: •IntrovaleTM active tablets are peach (Day 1 to Day 84). •IntrovaleTM inactive tablets are white (Day 85 to Day 91). Sunday Start: For each 91-day course, take in the following order: •Take the first peach tablet (0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol) on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, take the tablet on that day. Due to the potential risk of becoming pregnant, use additional non-hormonal contraception (such as condoms or spermicide) for the first 7 days of treatment. •Take subsequent peach tablets once daily at the same time each day for a total of 84 days. •Take one white tablet (inert) daily for the following 7 days and at the same time of day that active tablets were taken. A scheduled period should occur during the 7 days that the white tablets are taken. •Begin the next and all subsequent 91-day courses of IntrovaleTM without interruption on the same day of the week (i.e., Sunday) on which the patient began her first dose. Follow the same schedule as the initial 91-day course: a peach tablet once a day for 84 days, and a white tablet once a day for 7 days. If the patient does not immediately start her next pill pack, instruct her to protect herself from pregnancy by using a non-hormonal back-up method of contraception until she has taken a peach tablet daily for 7 consecutive days. Switching to IntrovaleTM from another oral contraceptive Start on the same day that a new pack of the previous oral contraceptive would have started. Switching from another contraceptive method to IntrovaleTM Start IntrovaleTM: • Transdermal patch On the day when the next application would have been scheduled. • Vaginal ring On the day when the next insertion would have been scheduled. • Injection On the day when the next injection would have been scheduled. • Intrauterine contraceptive (IUD) On the day of removal. If the IUD is not removed on first day of the patient’s menstrual cycle, additional non- hormonal contraception (such as condoms or spermicide) is needed for the first seven days of the first 91-day course. days of the first 91-day course. • Implant On the day of removal. Complete instructions to facilitate patient counseling on proper tablet usage are located in the FDA-approved patient labeling. Starting IntrovaleTM after Abortion or Miscarriage First-trimester •After a first-trimester abortion or miscarriage, IntrovaleTM may be started immediately. An additional method of contraception is not needed if IntrovaleTM is started immediately. •If IntrovaleTM is not started within 5 days after termination of the pregnancy, the patient should use additional non-hormonal contraception (such as condoms or spermicide) for the first seven days of her first 91-day course of IntrovaleTM. Second-trimester •Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start IntrovaleTM following the instructions in Table 1 for Sunday start. Use additional non-hormonal contraception (such as condoms or spermicide) for the first seven days of the patient’s first 91-day course of IntrovaleTM [see Contraindications (4), Warnings and Precautions (5.1), and FDA-approved Patient Labeling]. Starting IntrovaleTM after Childbirth •Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with IntrovaleTM following the instructions in Table 1 for women not currently using hormonal contraception. •IntrovaleTM is not recommended for use in lactating women [see Use in Specific Populations (8.3) and FDA-Approved Patient Labeling]. •If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of IntrovaleTM [see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.1 and 8.3), and FDA-approved Patient Labeling]. Tablet Dispenser Instructions: •The Tablet Dispenser consists of a Tri-Fold Buler Card that holds 91 individually sealed pills (a 13-week, or 91-day, cycle). The 91 pills consist of 84 peach pills (active pills with hormones) and 7 white pills (inactive pills without hormone) arranged in 12 rows of 7 tablets each, labeled weeks “START” through “Week 12” (active pills with hormones) followed by 1 row of 7 white pills, labeled “Week 13” (inactive pills without hormone) •Advise the patient to remove the first pill in the upper left corner by pushing down on the pill. The pill will come out through a hole in the back of the Tablet Dispenser. •Advise the patient to wait 24 hours to take the next pill, and continue to take one pill each day until all the pills have been taken. •Advise the patient, after taking the last white pill, to start taking the first peach pill from a new Tablet Dispenser the very next day, regardless of when their period started.

•Stop levonorgestrel and ethinyl estradiol if an arterial thrombotic event or venous thromboembolic (VTE) event occurs. •Stop levonorgestrel and ethinyl estradiol if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. •If feasible, stop levonorgestrel and ethinyl estradiol at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE as well as during and following prolonged immobilization. •Start levonorgestrel and ethinyl estradiol no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum VTE decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. •The use of COCs increases the risk of VTE. However, pregnancy increases the risk of VTE as much or more than the use of COCs. The risk of VTE in women using COCs is 3 to 9 cases per 10,000 woman- years. The risk of VTE is highest during the first year of use of COCs and when restarting hormonal contraception after a break of 4 weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after use is discontinued. •Use of levonorgestrel and ethinyl estradiol provides women with more hormonal exposure on a yearly basis than conventional monthly COCs containing the same strength synthetic estrogens and progestins (an additional 9 weeks of exposure per year). In the clinical trial, one case of pulmonary embolism was reported. Postmarketing adverse reactions of VTE have been reported in women who used levonorgestrel and ethinyl estradiol. •Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. Stroke has been reported in women associated with the use of levonorgestrel and ethinyl estradiol. COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes). This risk increases with age, particularly in women over 35 years of age who smoke. •Use COCs with caution in women with cardiovascular disease risk factors.

Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs may worsen existing gallbladder disease. A past history of COC-related cholestasis predicts an increased risk with subsequent COC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for COC-related cholestasis.

Bleeding and/or spotting that occurs at any time while taking the first 84 tablets of each extended-cycle regimen is considered “unscheduled” bleeding/spotting. Bleeding that occurs during the time a woman takes the seven white inert tablets is considered “scheduled” bleeding. Unscheduled and Scheduled Bleeding and Spotting Unscheduled (breakthrough) bleeding and spotting sometimes occur in patients on COCs, especially during the first 3 months of use. If unscheduled bleeding persists or occurs after previously regular cycles on levonorgestrel and ethinyl estradiol, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC. Before prescribing levonorgestrel and ethinyl estradiol, advise the woman to weigh the convenience of fewer scheduled menses (4 per year instead of 13 per year) against the inconvenience of increased unscheduled bleeding and/or spotting. The clinical trial of the efficacy of levonorgestrel and ethinyl estradiol (91-day cycles) in preventing pregnancy also assessed scheduled and unscheduled bleeding. The participants in the study were composed primarily of women who had used oral contraceptives previously as opposed to new users. Women with a history of breakthrough bleeding/spotting ≥ 10 consecutive days on oral contraceptives were excluded from the study. More levonorgestrel and ethinyl estradiol subjects, compared to subjects on the comparator 28-day cycle regimen, discontinued prematurely for unacceptable bleeding (7.7% [levonorgestrel and ethinyl estradiol] vs. 1.8% [28-day cycle regimen]). Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. Table 3 below presents the number of days with unscheduled bleeding and/or spotting for each respective 91-day cycle.   Table 3 Number of Unscheduled Bleeding and/or Spotting Days per 91-day Cycle Cycle (N) Days of Unscheduled Bleeding and/or Spotting per 84-Day Interval Median Days Per Subject- Month Mean Q1 Median Q3 1 (446) 15.1 3 12 23 3 2 (368) 11.6 2 6 17.5 1.5 3 (309) 10.6 1 6 15 1.5 4 (282) 8.8 1 4 14 1 Q1=Quartile 1: 25% of women had ≤ this number of days of unscheduled bleeding/spotting Median: 50% of women had ≤ this number of days of unscheduled bleeding/spotting Q3=Quartile 3: 75% of women had ≤ this number of days of unscheduled bleeding/spotting Table 4 shows the percentages of women with ≥7 days and ≥20 days of unscheduled spotting and/or bleeding in the levonorgestrel and ethinyl estradiol and the 28-day cycle treatment groups.   Table 4 Percentage of Subjects with Unscheduled Bleeding and/or Spotting Days of unscheduled bleeding and/or spotting Percentage of Subjectsa Levonorgestrel and Ethinyl Estradiol Cycle 1 (N=385) Cycle 4 (N=261) ≥7 days 65% 42% ≥20 days 35% 15% 28-day regimen Cycle 1-4 (N=194) Cycle 10-13 (N=158) ≥7 days 38% 39% ≥20 days 6% 4% aBased on spotting and/or bleeding on days 1 to 84 of a 91 day cycle in the levonorgestrel and ethinyl estradiol subjects and days 1 to 21 of a 28 day cycle over 4 cycles in the 28-day dosing regimen. Total days of bleeding and/or spotting (scheduled plus unscheduled) were similar over one year of treatment for levonorgestrel and ethinyl estradiol subjects and subjects on the 28-day cycle regimen. Amenorrhea and Oligomenorrhea Women who are not pregnant and use levonorgestrel and ethinyl estradiol may experience amenorrhea. Based on data from the clinical trial, amenorrhea occurred in approximately 0.8% of women during Cycle 1, 1.2% of women during Cycle 2, 3.7% of women during Cycle 3, and 3.4% of women during Cycle 4. Because women using levonorgestrel and ethinyl estradiol will likely have scheduled bleeding only 4 times per year, rule out pregnancy at the time of any missed menstrual period. Some women may experience amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was pre-existent.

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. Discontinue levonorgestrel and ethinyl estradiol use if pregnancy is confirmed.

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. Discontinue levonorgestrel and ethinyl estradiol use if pregnancy is confirmed. Administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations (8.1)].

There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy.

There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy. Do not administer COCs to induce withdrawal bleeding as a test for pregnancy. Do not use COCs during pregnancy to treat threatened or habitual abortion.

Advise the nursing mother to use other forms of contraception, when possible, until she has weaned her child. COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk.

COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.

COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.