Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied RIVELSA (levonorgestrel/ethinyl estradiol and ethinyl estradiol) tablets are available as round, film-coated, unscored, biconvex tablets debossed with TV on one side, packaged in an Extended-Cycle Tablet Dispenser, each containing a 13-week supply of the tablets in the following order: 42 light pink tablets, each containing 0.15 mg of levonorgestrel and 0.02 mg ethinyl estradiol: debossed with 076 on the other side 21 pink tablets containing 0.15 mg of levonorgestrel and 0.025 mg ethinyl estradiol: debossed with 075 on the other side 21 purple tablets containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol: debossed with 074 on the other side and 7 yellow tablets containing 0.01 mg of ethinyl estradiol: debossed with 077 on the other side Box of 2 Extended-Cycle Tablet Dispensers NDC 0093-6031-82 Storage and Handling Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature].; Package/Label Display Panel, Part 1 of 2 NDC 0093- 6031 -82 RIVELSA™ (levonorgestrel/ethinyl estradiol) tablets 0.15 mg/0.02 mg, 0.15 mg/0.025 mg, 0.15 mg/0.03 mg (ethinyl estradiol) tablets 0.01 mg Usual Dosage: One tablet daily for 91 consecutive days in the following order: 42 light pink tablets each containing 0.15 mg levonorgestrel and 0.02 mg ethinyl estradiol, 21 pink tablets each containing 0.15 mg of levonorgestrel and 0.025 mg ethinyl estradiol, and 21 purple tablets each containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol, and 7 yellow tablets each containing 0.01 mg of ethinyl estradiol. Pharmacist: Dispense patient information with each prescription. Rx only 2 Extended-Cycle Tablet Dispensers, 91 Tablets Each TEVA carton image 1; Package/Label Display Panel, Part 2 of 2 NDC 0093- 6031 -82 RIVELSA™ (levonorgestrel/ethinyl estradiol) tablets 0.15 mg/0.02 mg, 0.15 mg/0.025 mg, 0.15 mg/0.03 mg (ethinyl estradiol) tablets 0.01 mg Usual Dosage: One tablet daily for 91 consecutive days in the following order: 42 light pink tablets each containing 0.15 mg levonorgestrel and 0.02 mg ethinyl estradiol, 21 pink tablets each containing 0.15 mg of levonorgestrel and 0.025 mg ethinyl estradiol, and 21 purple tablets each containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol, and 7 yellow tablets each containing 0.01 mg of ethinyl estradiol. Pharmacist: Dispense patient information with each prescription. Rx only 2 Extended-Cycle Tablet Dispensers, 91 Tablets Each TEVA carton image 2
- 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied RIVELSA (levonorgestrel/ethinyl estradiol and ethinyl estradiol) tablets are available as round, film-coated, unscored, biconvex tablets debossed with TV on one side, packaged in an Extended-Cycle Tablet Dispenser, each containing a 13-week supply of the tablets in the following order: 42 light pink tablets, each containing 0.15 mg of levonorgestrel and 0.02 mg ethinyl estradiol: debossed with 076 on the other side 21 pink tablets containing 0.15 mg of levonorgestrel and 0.025 mg ethinyl estradiol: debossed with 075 on the other side 21 purple tablets containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol: debossed with 074 on the other side and 7 yellow tablets containing 0.01 mg of ethinyl estradiol: debossed with 077 on the other side Box of 2 Extended-Cycle Tablet Dispensers NDC 0093-6031-82 Storage and Handling Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature].
- Package/Label Display Panel, Part 1 of 2 NDC 0093- 6031 -82 RIVELSA™ (levonorgestrel/ethinyl estradiol) tablets 0.15 mg/0.02 mg, 0.15 mg/0.025 mg, 0.15 mg/0.03 mg (ethinyl estradiol) tablets 0.01 mg Usual Dosage: One tablet daily for 91 consecutive days in the following order: 42 light pink tablets each containing 0.15 mg levonorgestrel and 0.02 mg ethinyl estradiol, 21 pink tablets each containing 0.15 mg of levonorgestrel and 0.025 mg ethinyl estradiol, and 21 purple tablets each containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol, and 7 yellow tablets each containing 0.01 mg of ethinyl estradiol. Pharmacist: Dispense patient information with each prescription. Rx only 2 Extended-Cycle Tablet Dispensers, 91 Tablets Each TEVA carton image 1
- Package/Label Display Panel, Part 2 of 2 NDC 0093- 6031 -82 RIVELSA™ (levonorgestrel/ethinyl estradiol) tablets 0.15 mg/0.02 mg, 0.15 mg/0.025 mg, 0.15 mg/0.03 mg (ethinyl estradiol) tablets 0.01 mg Usual Dosage: One tablet daily for 91 consecutive days in the following order: 42 light pink tablets each containing 0.15 mg levonorgestrel and 0.02 mg ethinyl estradiol, 21 pink tablets each containing 0.15 mg of levonorgestrel and 0.025 mg ethinyl estradiol, and 21 purple tablets each containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol, and 7 yellow tablets each containing 0.01 mg of ethinyl estradiol. Pharmacist: Dispense patient information with each prescription. Rx only 2 Extended-Cycle Tablet Dispensers, 91 Tablets Each TEVA carton image 2
Overview
RIVELSA (levonorgestrel/ethinyl estradiol and ethinyl estradiol) tablets is an extended-cycle oral contraceptive. RIVELSA consists of 42 light pink tablets containing 0.15 mg levonorgestrel and 0.02 mg ethinyl estradiol, 21 pink tablets containing 0.15 mg levonorgestrel and 0.025 mg ethinyl estradiol, and 21 purple tablets containing 0.15 mg levonorgestrel and 0.03 mg ethinyl estradiol, and 7 yellow tablets containing 0.01 mg ethinyl estradiol. Levonorgestrel is a progestin and ethinyl estradiol is an estrogen. The structural formulas, molecular formulas, molecular weights, and chemical names for the active components are shown below: Levonorgestrel C 21 H 28 O 2 MW: 312.4 Levonorgestrel is chemically 18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-(17α)-(-)-. Ethinyl Estradiol C 20 H 24 O 2 MW: 296.4 Ethinyl Estradiol is 19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-. Each light pink tablet contains the following inactive ingredients: anhydrous lactose, D&C Red no. 27/phloxine aluminum lake, FD&C Blue no. 2/Indigo Carmine aluminum lake, FD&C Yellow no. 6/Sunset Yellow FCF aluminum lake, hypromellose, lactose monohydrate, microcrystalline cellulose, magnesium stearate, polyethylene glycol/macrogol, titanium dioxide, and triacetin. Each pink tablet contains the following inactive ingredients: anhydrous lactose, D&C Red no. 27/phloxine aluminum lake, FD&C Blue no. 2/Indigo Carmine aluminum lake, hypromellose, lactose monohydrate, microcrystalline cellulose, magnesium stearate, polyethylene glycol/macrogol, titanium dioxide and triacetin. Each purple tablet contains the following inactive ingredients: anhydrous lactose, D&C Red no. 27/phloxine aluminum lake, FD&C Blue no. 1/Brilliant Blue FCF aluminum lake, hypromellose, lactose monohydrate, microcrystalline cellulose, magnesium stearate, polyethylene glycol/macrogol, titanium dioxide and triacetin. Each yellow tablet contains the following inactive ingredients: anhydrous lactose, D&C Yellow no. 10 aluminum lake, FD&C Yellow no. 6/Sunset Yellow FCF aluminum lake, hypromellose, magnesium stearate, microcrystalline cellulose, polacrilin potassium, polyethylene glycol/macrogol, polysorbate 80 and titanium dioxide. levonorgestril structure ethinyl estradiol structure
Indications & Usage
RIVELSA ® is indicated for use by females of reproductive age to prevent pregnancy. RIVELSA is a combination of levonorgestrel, a progestin, and ethinyl estradiol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy. ( 1 )
Dosage & Administration
Take one tablet daily by mouth at the same time every day for 91 days in the order directed on the blister pack. ( 2 ) 2.1 How to Start and Take RIVELSA Begin RIVELSA on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, take the first light pink tablet that day. For each 91-day course, take in the following order: Start the first light pink tablet on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, take the tablet on that day. Then take one light pink tablet once daily for a total of 42 consecutive days. Use a non-hormonal backup method of contraception (such as condoms and spermicide) for the first 7 days of treatment. One pink tablet once daily for 21 consecutive days. One purple tablet once daily for 21 days. One yellow tablet once daily for 7 days. Bleeding should occur during yellow tablet use. Begin the next and all subsequent 91-day courses of RIVELSA without interruption on the same day of the week (Sunday) on which the first dose of RIVELSA was taken. Follow the same schedule as the initial 91-day course: light pink tablet once daily for 42 days, pink tablet once daily for 21 days, purple tablet once daily for 21 days, and yellow tablet once daily for 7 days. If the next pill pack is not started immediately, use a non-hormonal backup method of contraception until a light pink tablet has been taken once daily for 7 consecutive days. Switching to RIVELSA from another oral hormonal contraceptive or from another contraceptive method (transdermal patch, vaginal ring, injection, intrauterine contraceptive, implant) Start on the Sunday after the patient’s next period starts. Use additional non-hormonal contraceptive (such as condoms and spermicide) until the patient has taken 7 light pink pills (7 days). Starting RIVELSA after Abortion or Miscarriage First-trimester RIVELSA may be started on the Sunday after an abortion or miscarriage. The patient must use additional non-hormonal contraception (such as condoms and spermicide) until the patient has taken a light pink tablet for 7 days. Second-trimester Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start contraceptive therapy with RIVELSA following the instructions for women not currently using hormonal contraception. Use additional non-hormonal contraception (such as condoms and spermicide) until the patient has taken a light pink tablet for 7 days [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )]. Starting RIVELSA after Childbirth Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with RIVELSA following the instructions for women not currently using hormonal contraception. Use additional non-hormonal contraception (such as condoms and spermicide) until the patient has taken a light pink tablet for 7 days [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )]. RIVELSA is not recommended for use in lactating women [see Use in Specific Populations ( 8.2 )] . If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of RIVELSA [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.1 )]. 2.2 Dosing RIVELSA Take one tablet by mouth at the same time every day. The dosage of RIVELSA is one light pink tablet once daily for 42 days, one pink tablet once daily for 21 days, one purple tablet once daily for 21 days, and one yellow tablet once daily for 7 days. To achieve maximum contraceptive effectiveness, take RIVELSA exactly as directed, in the order directed, and at intervals not exceeding 24 hours. The failure rate may increase when pills are missed or taken incorrectly. 2.3 Missed Doses Table 1. Instructions for Missed RIVELSA Tablets If one light pink, pink or purple tablet is missed Take the missed tablet as soon as possible. Take the next tablet at the regular time. Continue taking one tablet a day until the pack is finished. A backup birth control method is not required if the patient has sex. If two light pink, pink or purple tablets in a row are missed Take the two missed tablets as soon as possible, and the next two tablets the next day. Continue taking one tablet a day until the pack is finished. Use additional nonhormonal contraception (such as condoms and spermicide) until tablets have been taken for 7 days after missing tablets. If three or more light pink, pink or purple tablets in a row are missed Throw away the missed tablets. Continue taking one tablet every day as indicated on the pack until the pack is finished. Bleeding may occur during the week following the missed tablets. Use additional nonhormonal contraception (such as condoms and spermicide) until tablets have been taken for 7 days after missing tablets. If any of the seven yellow tablets are missed Throw away the missed tablets. Continue taking the remaining tablets until the pack is finished. A backup birth control method is not needed. 2.4 Advice in Case of Gastrointestinal Disturbances In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting or diarrhea occurs within 3-4 hours after taking a light pink, pink or purple tablet, handle this as a missed tablet [see Dosage and Administration ( 2.3 )] . 2.1 How to Start and Take RIVELSA Begin RIVELSA on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, take the first light pink tablet that day. For each 91-day course, take in the following order: Start the first light pink tablet on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, take the tablet on that day. Then take one light pink tablet once daily for a total of 42 consecutive days. Use a non-hormonal backup method of contraception (such as condoms and spermicide) for the first 7 days of treatment. One pink tablet once daily for 21 consecutive days. One purple tablet once daily for 21 days. One yellow tablet once daily for 7 days. Bleeding should occur during yellow tablet use. Begin the next and all subsequent 91-day courses of RIVELSA without interruption on the same day of the week (Sunday) on which the first dose of RIVELSA was taken. Follow the same schedule as the initial 91-day course: light pink tablet once daily for 42 days, pink tablet once daily for 21 days, purple tablet once daily for 21 days, and yellow tablet once daily for 7 days. If the next pill pack is not started immediately, use a non-hormonal backup method of contraception until a light pink tablet has been taken once daily for 7 consecutive days. Switching to RIVELSA from another oral hormonal contraceptive or from another contraceptive method (transdermal patch, vaginal ring, injection, intrauterine contraceptive, implant) Start on the Sunday after the patient’s next period starts. Use additional non-hormonal contraceptive (such as condoms and spermicide) until the patient has taken 7 light pink pills (7 days). Starting RIVELSA after Abortion or Miscarriage First-trimester RIVELSA may be started on the Sunday after an abortion or miscarriage. The patient must use additional non-hormonal contraception (such as condoms and spermicide) until the patient has taken a light pink tablet for 7 days. Second-trimester Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start contraceptive therapy with RIVELSA following the instructions for women not currently using hormonal contraception. Use additional non-hormonal contraception (such as condoms and spermicide) until the patient has taken a light pink tablet for 7 days [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )]. Starting RIVELSA after Childbirth Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with RIVELSA following the instructions for women not currently using hormonal contraception. Use additional non-hormonal contraception (such as condoms and spermicide) until the patient has taken a light pink tablet for 7 days [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )]. RIVELSA is not recommended for use in lactating women [see Use in Specific Populations ( 8.2 )] . If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of RIVELSA [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.1 )]. 2.2 Dosing RIVELSA Take one tablet by mouth at the same time every day. The dosage of RIVELSA is one light pink tablet once daily for 42 days, one pink tablet once daily for 21 days, one purple tablet once daily for 21 days, and one yellow tablet once daily for 7 days. To achieve maximum contraceptive effectiveness, take RIVELSA exactly as directed, in the order directed, and at intervals not exceeding 24 hours. The failure rate may increase when pills are missed or taken incorrectly. 2.3 Missed Doses Table 1. Instructions for Missed RIVELSA Tablets If one light pink, pink or purple tablet is missed Take the missed tablet as soon as possible. Take the next tablet at the regular time. Continue taking one tablet a day until the pack is finished. A backup birth control method is not required if the patient has sex. If two light pink, pink or purple tablets in a row are missed Take the two missed tablets as soon as possible, and the next two tablets the next day. Continue taking one tablet a day until the pack is finished. Use additional nonhormonal contraception (such as condoms and spermicide) until tablets have been taken for 7 days after missing tablets. If three or more light pink, pink or purple tablets in a row are missed Throw away the missed tablets. Continue taking one tablet every day as indicated on the pack until the pack is finished. Bleeding may occur during the week following the missed tablets. Use additional nonhormonal contraception (such as condoms and spermicide) until tablets have been taken for 7 days after missing tablets. If any of the seven yellow tablets are missed Throw away the missed tablets. Continue taking the remaining tablets until the pack is finished. A backup birth control method is not needed.
Warnings & Precautions
Vascular risks: Stop if a thrombotic or thromboembolic event occurs. Stop at least 4 weeks before and through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breastfeeding. Consider cardiovascular risk factors before initiating in all females, particularly those over 35 years. ( 5.1 , 5.5 ) Liver disease: Discontinue if jaundice occurs. ( 5.2 ) Hypertension: If used in females with well-controlled hypertension, monitor blood pressure and stop use if blood pressure rises significantly. ( 5.3 ) Gallbladder disease: May cause or worsen gallbladder disease. ( 5.6 ) Carbohydrate and lipid metabolic effects: Monitor glucose in prediabetic and diabetic women taking RIVELSA. Consider an alternate contraceptive method for women with uncontrolled dyslipidemias. ( 5.7 ) Headache: Evaluate significant change in headaches and discontinue if indicated. ( 5.8 ) Uterine bleeding: May cause irregular bleeding or amenorrhea. Evaluate for other causes if symptoms persist. ( 5.9 ) 5.1 Thromboembolic Disorders and Other Vascular Conditions Stop RIVELSA if an arterial or deep venous thromboembolic event occurs. Stop RIVELSA if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. Discontinue RIVELSA during prolonged immobilization. If feasible, stop RIVELSA at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism. Start RIVELSA no earlier than 4 weeks after delivery, in females who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. Before starting RIVELSA evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. RIVELSA is contraindicated in females with a high risk of arterial or venous/thromboembolic diseases [see Contraindications ( 4 )] . Arterial Events COCs increase the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke. The risk is greater among older women (> 35 years of age), smokers, and females with hypertension, dyslipidemia, diabetes, or obesity. RIVELSA is contraindicated in women over 35 years of age who smoke [see Contraindications (4)] . Cigarette smoking increases the risk of serious cardiovascular events from COC use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. Venous Events Use of COCs increases the risk of venous thromboembolic events (VTEs), such as deep vein thrombosis and pulmonary embolism. Risk factors for VTEs include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of COCs [see Contraindications (4)] . While the increased risk of VTE associated with use of COCs is well-established, the rates of VTE are even greater during pregnancy, and especially during the postpartum period (see Figure 1). The rate of VTE in females using COCs has been estimated to be 3 to 9 cases per 10,000 woman years. The risk of VTE is highest during the first year of use of a COC and when restarting hormonal contraception after a break of four weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued. Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use oral contraceptives, for females who use oral contraceptives, and for females in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 females who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these females will develop a VTE. Use of RIVELSA provides women with more hormonal exposure on a yearly basis than conventional monthly oral contraceptives containing the same strength synthetic estrogens and progestins (an additional 9 and 13 weeks of exposure to progestin and estrogen, respectively, per year). In the clinical trial, three cases of deep vein thrombosis were reported. Figure 1 Likelihood of developing a VTE 5.2 Liver Disease Elevated Liver Enzymes RIVELSA is contraindicated in females with acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see Contraindications ( 4 )]. Acute liver test abnormalities may necessitate the discontinuation of RIVELSA until liver tests return to normal and RIVELSA causation has been excluded. Discontinue RIVELSA if jaundice develops. Liver Tumors RIVELSA is contraindicated in females with benign or malignant liver tumors [see Contraindications ( 4 )]. COCs increase the risk of hepatic adenomas. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death from abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users. The attributable risk of liver cancers in COC users is less than one case per million users. 5.3 Hypertension RIVELSA is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see Contraindications ( 4 )] . For all females, including those with well-controlled hypertension, monitor blood pressure at routine visits and stop RIVELSA if blood pressure rises significantly. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The effect of COCs on blood pressure may vary according to the progestin in the COC. 5.4 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 RIVELSA. Discontinue RIVELSA prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications ( 4 )] . RIVELSA can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen. 5.5 Age-related Considerations The risk for cardiovascular disease and prevalence of risk factors for cardiovascular disease increases with age. Certain conditions, such as smoking and migraine headache without aura, that do not contraindicate COC use in younger females, are contraindications to use in women over 35 years of age [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . Consider the presence of underlying risk factors that may increase the risk of cardiovascular disease or VTE, particularly before initiating RIVELSA for women over 35 years, such as: Hypertension Diabetes Dyslipidemia Obesity 5.6 Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs, including RIVELSA, may also 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. 5.7 Adverse Carbohydrate and Lipid Metabolic Effects Hyperglycemia RIVELSA is contraindicated in diabetic women over age 35, or females who have diabetes with hypertension, nephropathy, retinopathy, neuropathy, other vascular disease, or females with diabetes of > 20 years duration [see Contraindications ( 4 )] . RIVELSA may decrease glucose tolerance. Carefully monitor prediabetic and diabetic females who are taking RIVELSA. Dyslipidemia Consider alternative contraception for females with uncontrolled dyslipidemias. RIVELSA may cause adverse lipid changes. Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using RIVELSA, which may increase the risk of pancreatitis. 5.8 Headache RIVELSA is contraindicated in females who have headaches with focal neurological symptoms or have migraine headaches with aura, and in women over 35 years of age who have migraine headaches with or without aura [see Contraindications ( 4 )] . If a woman taking RIVELSA develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue RIVELSA if indicated. Consider discontinuation of RIVELSA in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) [see Contraindications ( 4 )] . 5.9 Bleeding Irregularities and Amenorrhea Bleeding and/or spotting that occurs at any time while taking the first 84 tablets (light pink, pink and purple) of each extended-cycle regimen is considered “unscheduled” bleeding/spotting. Bleeding that occurs during the time a woman takes the seven tablets (yellow) containing 10 mcg of ethinyl estradiol is considered “scheduled” bleeding. Unscheduled and Scheduled Bleeding and Spotting Females using RIVELSA may experience unscheduled (breakthrough or intracyclic) bleeding and spotting, especially during the first 3 months of use. Bleeding irregularities may resolve over time or by changing to a different contraceptive product. If unscheduled bleeding persists or occurs after previously regular cycles on RIVELSA, evaluate for causes such as pregnancy or malignancy. When prescribing RIVELSA, consider the occurrence of fewer scheduled menses (4 per year instead of 13 per year) against the occurrence of increased unscheduled bleeding and/or spotting. A 12-month open-label study of the efficacy of RIVELSA in preventing pregnancy assessed scheduled and unscheduled bleeding [see Clinical Studies ( 14 )] in 3,597 women who completed 34,087 28-day cycles of exposure. A total of 178 (4.9%) of the women discontinued RIVELSA, at least in part, due to bleeding and/or spotting. Scheduled (withdrawal) bleeding and/or spotting remained fairly stable over time, with an average of 3 to 4 days of bleeding and/or spotting per each 91-day cycle. Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. Table 2 below presents the number of days with unscheduled bleeding, spotting, and unscheduled bleeding and/or spotting in Treatment Cycles 1 to 4. Table 2: Number of Unscheduled Bleeding, Spotting and Bleeding and/or Spotting Days per 91-day Cycle Cycle (N) Days of Unscheduled Bleeding per 84-Day Interval Median Days Per Subject-Month Mean Q1 Median Q3 1 (3330) 7.2 0 4 10 1.0 2 (2820) 3.3 0 0 4 0.0 3 (2433) 2.5 0 0 3 0.0 4 (2213) 2.2 0 0 2 0.0 Cycle (N) Days of Unscheduled Spotting per 84-Day Interval Median Days Per Subject-Month Mean Q1 Median Q3 1 (3330) 10.7 2 7 15 1.8 2 (2820) 6.7 0 3 9 0.8 3 (2433) 5.2 0 2 6 0.5 4 (2213) 4.4 0 1 5 0.3 Cycle (N) Days of Unscheduled Bleeding and/or Spotting per 84-Day Interval Median Days Per Subject-Month Mean Q1 Median Q3 1 (3330) 17.9 5 14 27 3.5 2 (2820) 10.0 1 5 14 1.3 3 (2433) 7.7 0 3 10 0.8 4 (2213) 6.6 0 3 8 0.8 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 Figure 2 shows the percent of RIVELSA subjects in the primary clinical trial with ≥7 days or ≥20 days of unscheduled bleeding and/or spotting, or just unscheduled bleeding, during each 91-day treatment cycle. Figure 2: Percent of Women Taking RIVELSA Who Reported Unscheduled Bleeding and/or Spotting If unscheduled spotting or bleeding occurs, instruct the patient to continue on the same regimen. If the bleeding is persistent or prolonged, advise the patient to consult her healthcare provider. Amenorrhea and Oligomenorrhea Females who use RIVELSA may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant. Based on data from the clinical trial, amenorrhea occurred in approximately 1.9% of women during Cycle 1, 7.7% during Cycle 2, 10.7% during Cycle 3, and 10.1% during Cycle 4 using RIVELSA. Rule out pregnancy in the event of amenorrhea. Some women may experience amenorrhea or oligomenorrhea after stopping RIVELSA, especially if these conditions were pre-existent. Figure 1 5.10 Depression Carefully observe females with a history of depression and discontinue RIVELSA if depression recurs to a serious degree. Six cases of suicidality (suicide attempts and suicidal behavior) were reported in the clinical trial; several of these cases occurred in women with a psychiatric history. Data on the association of COCs with onset of depression or exacerbation of existing depression are limited. 5.11 Malignant Neoplasms Breast Cancer RIVELSA is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications ( 4 )] . 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 ( 6.2 )] . Cervical Cancer Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings are due to differences in sexual behavior and other factors. 5.12 Effect on Binding Globulins The estrogen component of RIVELSA may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased. 5.13 Hereditary Angioedema In women with hereditary angioedema, exogenous estrogens, including RIVELSA, may induce or exacerbate symptoms of hereditary angioedema. 5.14 Chloasma Chloasma may occur with RIVELSA use, especially in females with a history of chloasma gravidarum. Advise females with a history of chloasma to avoid exposure to the sun or ultraviolet radiation while taking RIVELSA. 5.1 Thromboembolic Disorders and Other Vascular Conditions Stop RIVELSA if an arterial or deep venous thromboembolic event occurs. Stop RIVELSA if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. Discontinue RIVELSA during prolonged immobilization. If feasible, stop RIVELSA at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism. Start RIVELSA no earlier than 4 weeks after delivery, in females who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. Before starting RIVELSA evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. RIVELSA is contraindicated in females with a high risk of arterial or venous/thromboembolic diseases [see Contraindications ( 4 )] . Arterial Events COCs increase the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke. The risk is greater among older women (> 35 years of age), smokers, and females with hypertension, dyslipidemia, diabetes, or obesity. RIVELSA is contraindicated in women over 35 years of age who smoke [see Contraindications (4)] . Cigarette smoking increases the risk of serious cardiovascular events from COC use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. Venous Events Use of COCs increases the risk of venous thromboembolic events (VTEs), such as deep vein thrombosis and pulmonary embolism. Risk factors for VTEs include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of COCs [see Contraindications (4)] . While the increased risk of VTE associated with use of COCs is well-established, the rates of VTE are even greater during pregnancy, and especially during the postpartum period (see Figure 1). The rate of VTE in females using COCs has been estimated to be 3 to 9 cases per 10,000 woman years. The risk of VTE is highest during the first year of use of a COC and when restarting hormonal contraception after a break of four weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued. Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use oral contraceptives, for females who use oral contraceptives, and for females in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 females who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these females will develop a VTE. Use of RIVELSA provides women with more hormonal exposure on a yearly basis than conventional monthly oral contraceptives containing the same strength synthetic estrogens and progestins (an additional 9 and 13 weeks of exposure to progestin and estrogen, respectively, per year). In the clinical trial, three cases of deep vein thrombosis were reported. Figure 1 Likelihood of developing a VTE 5.2 Liver Disease Elevated Liver Enzymes RIVELSA is contraindicated in females with acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see Contraindications ( 4 )]. Acute liver test abnormalities may necessitate the discontinuation of RIVELSA until liver tests return to normal and RIVELSA causation has been excluded. Discontinue RIVELSA if jaundice develops. Liver Tumors RIVELSA is contraindicated in females with benign or malignant liver tumors [see Contraindications ( 4 )]. COCs increase the risk of hepatic adenomas. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death from abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users. The attributable risk of liver cancers in COC users is less than one case per million users. 5.3 Hypertension RIVELSA is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see Contraindications ( 4 )] . For all females, including those with well-controlled hypertension, monitor blood pressure at routine visits and stop RIVELSA if blood pressure rises significantly. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The effect of COCs on blood pressure may vary according to the progestin in the COC. 5.4 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 RIVELSA. Discontinue RIVELSA prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications ( 4 )] . RIVELSA can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen. 5.6 Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs, including RIVELSA, may also 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. 5.7 Adverse Carbohydrate and Lipid Metabolic Effects Hyperglycemia RIVELSA is contraindicated in diabetic women over age 35, or females who have diabetes with hypertension, nephropathy, retinopathy, neuropathy, other vascular disease, or females with diabetes of > 20 years duration [see Contraindications ( 4 )] . RIVELSA may decrease glucose tolerance. Carefully monitor prediabetic and diabetic females who are taking RIVELSA. Dyslipidemia Consider alternative contraception for females with uncontrolled dyslipidemias. RIVELSA may cause adverse lipid changes. Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using RIVELSA, which may increase the risk of pancreatitis. 5.8 Headache RIVELSA is contraindicated in females who have headaches with focal neurological symptoms or have migraine headaches with aura, and in women over 35 years of age who have migraine headaches with or without aura [see Contraindications ( 4 )] . If a woman taking RIVELSA develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue RIVELSA if indicated. Consider discontinuation of RIVELSA in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) [see Contraindications ( 4 )] . 5.9 Bleeding Irregularities and Amenorrhea Bleeding and/or spotting that occurs at any time while taking the first 84 tablets (light pink, pink and purple) of each extended-cycle regimen is considered “unscheduled” bleeding/spotting. Bleeding that occurs during the time a woman takes the seven tablets (yellow) containing 10 mcg of ethinyl estradiol is considered “scheduled” bleeding. Unscheduled and Scheduled Bleeding and Spotting Females using RIVELSA may experience unscheduled (breakthrough or intracyclic) bleeding and spotting, especially during the first 3 months of use. Bleeding irregularities may resolve over time or by changing to a different contraceptive product. If unscheduled bleeding persists or occurs after previously regular cycles on RIVELSA, evaluate for causes such as pregnancy or malignancy. When prescribing RIVELSA, consider the occurrence of fewer scheduled menses (4 per year instead of 13 per year) against the occurrence of increased unscheduled bleeding and/or spotting. A 12-month open-label study of the efficacy of RIVELSA in preventing pregnancy assessed scheduled and unscheduled bleeding [see Clinical Studies ( 14 )] in 3,597 women who completed 34,087 28-day cycles of exposure. A total of 178 (4.9%) of the women discontinued RIVELSA, at least in part, due to bleeding and/or spotting. Scheduled (withdrawal) bleeding and/or spotting remained fairly stable over time, with an average of 3 to 4 days of bleeding and/or spotting per each 91-day cycle. Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. Table 2 below presents the number of days with unscheduled bleeding, spotting, and unscheduled bleeding and/or spotting in Treatment Cycles 1 to 4. Table 2: Number of Unscheduled Bleeding, Spotting and Bleeding and/or Spotting Days per 91-day Cycle Cycle (N) Days of Unscheduled Bleeding per 84-Day Interval Median Days Per Subject-Month Mean Q1 Median Q3 1 (3330) 7.2 0 4 10 1.0 2 (2820) 3.3 0 0 4 0.0 3 (2433) 2.5 0 0 3 0.0 4 (2213) 2.2 0 0 2 0.0 Cycle (N) Days of Unscheduled Spotting per 84-Day Interval Median Days Per Subject-Month Mean Q1 Median Q3 1 (3330) 10.7 2 7 15 1.8 2 (2820) 6.7 0 3 9 0.8 3 (2433) 5.2 0 2 6 0.5 4 (2213) 4.4 0 1 5 0.3 Cycle (N) Days of Unscheduled Bleeding and/or Spotting per 84-Day Interval Median Days Per Subject-Month Mean Q1 Median Q3 1 (3330) 17.9 5 14 27 3.5 2 (2820) 10.0 1 5 14 1.3 3 (2433) 7.7 0 3 10 0.8 4 (2213) 6.6 0 3 8 0.8 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 Figure 2 shows the percent of RIVELSA subjects in the primary clinical trial with ≥7 days or ≥20 days of unscheduled bleeding and/or spotting, or just unscheduled bleeding, during each 91-day treatment cycle. Figure 2: Percent of Women Taking RIVELSA Who Reported Unscheduled Bleeding and/or Spotting If unscheduled spotting or bleeding occurs, instruct the patient to continue on the same regimen. If the bleeding is persistent or prolonged, advise the patient to consult her healthcare provider. Amenorrhea and Oligomenorrhea Females who use RIVELSA may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant. Based on data from the clinical trial, amenorrhea occurred in approximately 1.9% of women during Cycle 1, 7.7% during Cycle 2, 10.7% during Cycle 3, and 10.1% during Cycle 4 using RIVELSA. Rule out pregnancy in the event of amenorrhea. Some women may experience amenorrhea or oligomenorrhea after stopping RIVELSA, especially if these conditions were pre-existent. Figure 1 5.10 Depression Carefully observe females with a history of depression and discontinue RIVELSA if depression recurs to a serious degree. Six cases of suicidality (suicide attempts and suicidal behavior) were reported in the clinical trial; several of these cases occurred in women with a psychiatric history. Data on the association of COCs with onset of depression or exacerbation of existing depression are limited. 5.11 Malignant Neoplasms Breast Cancer RIVELSA is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications ( 4 )] . 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 ( 6.2 )] . Cervical Cancer Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings are due to differences in sexual behavior and other factors. 5.12 Effect on Binding Globulins The estrogen component of RIVELSA may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased. 5.13 Hereditary Angioedema In women with hereditary angioedema, exogenous estrogens, including RIVELSA, may induce or exacerbate symptoms of hereditary angioedema. 5.14 Chloasma Chloasma may occur with RIVELSA use, especially in females with a history of chloasma gravidarum. Advise females with a history of chloasma to avoid exposure to the sun or ultraviolet radiation while taking RIVELSA.
Boxed Warning
CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs, including RIVELSA, are contraindicated in women who are over 35 years of age and smoke [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS See full prescribing information for complete boxed warning. RIVELSA is contraindicated in women over 35 years old who smoke. ( 4 ) Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. ( 4 )
Contraindications
RIVELSA is contraindicated in females who are known to have or develop the following conditions: A high risk of arterial or venous thrombotic diseases. Examples include females who are known to: Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions ( 5.1 )]. Have current or history of deep vein thrombosis or pulmonary embolism [see Warnings and Precautions ( 5.1 )]. Have cerebrovascular disease [see Warnings and Precautions ( 5.1 )]. Have coronary artery disease [see Warnings and Precautions ( 5.1 )]. Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions ( 5.1 )]. Have inherited or acquired hypercoagulopathies [see Warnings and Precautions ( 5.1 )]. Have uncontrolled hypertension or hypertension with vascular disease [see Warnings and Precautions ( 5.5 )]. Have diabetes mellitus and are over age 35, diabetes mellitus with hypertension or with vascular disease or other end-organ damage, or diabetes mellitus of > 20 years duration [see Warnings and Precautions ( 5.7 )]. Have headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches [see Warnings and Precautions ( 5.8 )]. Current diagnosis of, or history of, breast cancer, which may be hormone sensitive [see Warnings and Precautions ( 5.11 )] . Liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.6 )]. Undiagnosed abnormal uterine bleeding [see Warnings and Precautions ( 5.9 )]. Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [see Warnings and Precautions ( 5.4 )]. A high risk of arterial or venous thrombotic diseases ( 4 ) Undiagnosed abnormal uterine bleeding ( 4 ) Breast cancer ( 4 ) Liver tumors or liver disease ( 4 ) Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4 )
Adverse Reactions
The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: Serious cardiovascular events [see Boxed Warning and Warnings and Precautions ( 5.1 )] Vascular events [see Warnings and Precautions ( 5.1 )] Liver disease [see Warnings and Precautions ( 5.2 )] The most common adverse reactions (≥2%) in clinical trials for RIVELSA were headaches, heavy/irregular vaginal bleeding, nausea/vomiting, acne, dysmenorrhea, weight increased, mood changes, anxiety/panic attack, breast pain and migraines. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described below are from a 12-month, US, open-label study, which enrolled women aged 18-40, of whom 3,597 took at least one dose of RIVELSA (2,661 woman-years of exposure) [see Clinical Studies ( 14 )] . Adverse Reactions Leading to Study Discontinuation : 13.3% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions (≥1% of women) leading to discontinuation were heavy/irregular bleeding (5.0%), mood swings/alteration/affect lability (1.4%), headaches/migraines (1.3%), weight increased (1.3%) and acne (1.0%). Common Adverse Reactions (≥2% of women) : headaches (12.2%), heavy/irregular vaginal bleeding (9.7%), nausea/vomiting (8.8%), acne (5.4%), dysmenorrhea (5.4%), weight increased (4.6%), mood changes (depression, depressed mood, crying, major depression, affective disorder, depression suicidal, dysthymic disorder) (2.9%), anxiety/panic attack (2.4%), breast tenderness/pain/discomfort (2.2%), migraine (2.0%). Serious Adverse Reactions (≥2 women): abortion spontaneous, suicide attempt, cholecystitis/cholelithiasis, deep vein thrombosis, ectopic pregnancy. 6.2 Postmarketing 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 - 1.12 (Figure 3). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 2). 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 - 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 8-10 years of COC use. Figure 3: Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives 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. The following adverse reactions have been identified during post-approval use of extended-cycle COCs containing levonorgestrel and ethinyl estradiol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal disorders: abdominal distension, vomiting General disorders and administration site conditions: chest pain, fatigue, malaise, edema peripheral, pain Immune system disorders: hypersensitivity reaction Investigations: blood pressure increased Musculoskeletal and connective tissue disorders: muscle spasms, pain in extremity Nervous system disorders: dizziness, loss of consciousness Psychiatric disorders: insomnia Reproductive and breast disorders: dysmenorrhea Respiratory, thoracic and mediastinal disorders: pulmonary embolism, pulmonary thrombosis Skin and subcutaneous tissue disorders: alopecia Vascular disorders: thrombosis Figure Breast cancer data 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described below are from a 12-month, US, open-label study, which enrolled women aged 18-40, of whom 3,597 took at least one dose of RIVELSA (2,661 woman-years of exposure) [see Clinical Studies ( 14 )] . Adverse Reactions Leading to Study Discontinuation : 13.3% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions (≥1% of women) leading to discontinuation were heavy/irregular bleeding (5.0%), mood swings/alteration/affect lability (1.4%), headaches/migraines (1.3%), weight increased (1.3%) and acne (1.0%). Common Adverse Reactions (≥2% of women) : headaches (12.2%), heavy/irregular vaginal bleeding (9.7%), nausea/vomiting (8.8%), acne (5.4%), dysmenorrhea (5.4%), weight increased (4.6%), mood changes (depression, depressed mood, crying, major depression, affective disorder, depression suicidal, dysthymic disorder) (2.9%), anxiety/panic attack (2.4%), breast tenderness/pain/discomfort (2.2%), migraine (2.0%). Serious Adverse Reactions (≥2 women): abortion spontaneous, suicide attempt, cholecystitis/cholelithiasis, deep vein thrombosis, ectopic pregnancy. 6.2 Postmarketing 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 - 1.12 (Figure 3). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 2). 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 - 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 8-10 years of COC use. Figure 3: Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives 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. The following adverse reactions have been identified during post-approval use of extended-cycle COCs containing levonorgestrel and ethinyl estradiol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal disorders: abdominal distension, vomiting General disorders and administration site conditions: chest pain, fatigue, malaise, edema peripheral, pain Immune system disorders: hypersensitivity reaction Investigations: blood pressure increased Musculoskeletal and connective tissue disorders: muscle spasms, pain in extremity Nervous system disorders: dizziness, loss of consciousness Psychiatric disorders: insomnia Reproductive and breast disorders: dysmenorrhea Respiratory, thoracic and mediastinal disorders: pulmonary embolism, pulmonary thrombosis Skin and subcutaneous tissue disorders: alopecia Vascular disorders: thrombosis Figure Breast cancer data
Drug Interactions
The sections below provide information on substances for which data on drug interactions with COCs are available. There is little information available about the clinical effect of most drug interactions that may affect COCs. However, based on the known pharmacokinetic effects of these drugs, clinical strategies to minimize any potential adverse effect on contraceptive effectiveness or safety are suggested. Consult the approved product labeling of all concurrently used drugs to obtain further information about interactions with COCs or the potential for metabolic enzyme or transporter system alterations. No drug-drug interaction studies were conducted with RIVELSA. Enzyme inducers (e.g., CYP3A4): May decrease the effectiveness of RIVELSA or increase breakthrough bleeding. Counsel patients to use a backup or alternative method of contraception when enzyme inducers are used with RIVELSA. ( 7.1 ) 7.1 Effects of Other Drugs on Combined Oral Contraceptives Substances Decreasing the Plasma Concentrations of COCs and Potentially Diminishing the Efficacy of COCs: Table 3 includes substances that demonstrated an important drug interaction with RIVELSA. Table 3: Significant Drug Interactions Involving Substances That Affect COCs Metabolic Enzyme Inducers Clinical effect Concomitant use of COCs with metabolic enzyme inducers may decrease the plasma concentrations of the estrogen and/or progestin component of COCs. Decreased exposure of the estrogen and/or progestin component of COCs may potentially diminish the effectiveness of COCs and may lead to contraceptive failure or an increase in breakthrough bleeding. Prevention or management Counsel females to use an alternative method of contraception or a backup method when enzyme inducers are used with COCs. Continue backup contraception for 28 days after discontinuing the enzyme inducer to maintain contraceptive reliability. Examples Aprepitant, barbiturates, bosentan, carbamazepine, efavirenz, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, rifabutin, rufinamide, topiramate, products containing St. John’s wort a , and certain protease inhibitors (see separate section on protease inhibitors below). Colesevelam Clinical effect Concomitant use of COCs with colesevelam significantly decreases systemic exposure of ethinyl estradiol. Decreased exposure of the estrogen component of COCs may potentially reduce contraceptive efficacy or result in an increase in breakthrough bleeding, depending on the strength of ethinyl estradiol in the COC. Prevention or management Administer 4 or more hours apart to attenuate this drug interaction. a Induction potency of St. John’s wort may vary widely based on preparation. Substances increasing the systemic exposure of COCs: Co-administration of atorvastatin or rosuvastatin and COCs containing ethinyl estradiol increase systemic exposure of ethinyl estradiol by approximately 20 to 25 percent. Ascorbic acid and acetaminophen may increase systemic exposure of ethinyl estradiol, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase systemic exposure of the estrogen and/or progestin component of COCs. Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant decreases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with some HIV protease inhibitors (e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir), some HCV protease inhibitors (e.g., boceprevir and telaprevir), and some non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine). In contrast, significant increases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with certain other HIV protease inhibitors (e.g., indinavir and atazanavir/ritonavir) and with other non-nucleoside reverse transcriptase inhibitors (e.g., etravirine). 7.2 Effects of Combined Oral Contraceptives on Other Drugs Table 4 provides significant drug interaction information for drugs co-administered with RIVELSA. Table 4: Significant Drug Interaction Information for Drugs Co-Administered With COCs Lamotrigine Clinical effect Concomitant use of COCs with lamotrigine may significantly decrease systemic exposure of lamotrigine due to induction of lamotrigine glucuronidation. Decreased systemic exposure of lamotrigine may reduce seizure control. Prevention or management Dose adjustment may be necessary. Consult the approved product labeling for lamotrigine. Thyroid Hormone Replacement Therapy or Corticosteroid Replacement Therapy Clinical effect Concomitant use of COCs with thyroid hormone replacement therapy or corticosteroid replacement therapy may increase systemic exposure of thyroid-binding and cortisol-binding globulin [see Warnings and Precautions ( 5.12 )] . Prevention or management The dose of replacement thyroid hormone or cortisol therapy may need to be increased. Consult the approved product labeling for the therapy in use [see Warnings and Precautions ( 5.12 )] . Other Drugs Clinical effect Concomitant use of COCs may decrease systemic exposure of acetaminophen, morphine, salicylic acid, and temazepam. Concomitant use with ethinyl estradiol-containing COCs may increase systemic exposure of other drugs (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole). Prevention or management The dosage of drugs that can be affected by this interaction may need to be increased. Consult the approved product labeling for the concomitantly used drug. 7.3 Concomitant Use with Hepatitis C Virus (HCV) Combination Therapy – Liver Enzyme Elevation Do not co-administer RIVELSA with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Warnings and Precautions ( 5.4 )] , and glecaprevir/pibrentasvir due to potential for ALT elevations . 7.4 Effect on Laboratory Tests The use of COCs may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. 7.1 Effects of Other Drugs on Combined Oral Contraceptives Substances Decreasing the Plasma Concentrations of COCs and Potentially Diminishing the Efficacy of COCs: Table 3 includes substances that demonstrated an important drug interaction with RIVELSA. Table 3: Significant Drug Interactions Involving Substances That Affect COCs Metabolic Enzyme Inducers Clinical effect Concomitant use of COCs with metabolic enzyme inducers may decrease the plasma concentrations of the estrogen and/or progestin component of COCs. Decreased exposure of the estrogen and/or progestin component of COCs may potentially diminish the effectiveness of COCs and may lead to contraceptive failure or an increase in breakthrough bleeding. Prevention or management Counsel females to use an alternative method of contraception or a backup method when enzyme inducers are used with COCs. Continue backup contraception for 28 days after discontinuing the enzyme inducer to maintain contraceptive reliability. Examples Aprepitant, barbiturates, bosentan, carbamazepine, efavirenz, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, rifabutin, rufinamide, topiramate, products containing St. John’s wort a , and certain protease inhibitors (see separate section on protease inhibitors below). Colesevelam Clinical effect Concomitant use of COCs with colesevelam significantly decreases systemic exposure of ethinyl estradiol. Decreased exposure of the estrogen component of COCs may potentially reduce contraceptive efficacy or result in an increase in breakthrough bleeding, depending on the strength of ethinyl estradiol in the COC. Prevention or management Administer 4 or more hours apart to attenuate this drug interaction. a Induction potency of St. John’s wort may vary widely based on preparation. Substances increasing the systemic exposure of COCs: Co-administration of atorvastatin or rosuvastatin and COCs containing ethinyl estradiol increase systemic exposure of ethinyl estradiol by approximately 20 to 25 percent. Ascorbic acid and acetaminophen may increase systemic exposure of ethinyl estradiol, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase systemic exposure of the estrogen and/or progestin component of COCs. Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant decreases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with some HIV protease inhibitors (e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir), some HCV protease inhibitors (e.g., boceprevir and telaprevir), and some non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine). In contrast, significant increases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with certain other HIV protease inhibitors (e.g., indinavir and atazanavir/ritonavir) and with other non-nucleoside reverse transcriptase inhibitors (e.g., etravirine). 7.2 Effects of Combined Oral Contraceptives on Other Drugs Table 4 provides significant drug interaction information for drugs co-administered with RIVELSA. Table 4: Significant Drug Interaction Information for Drugs Co-Administered With COCs Lamotrigine Clinical effect Concomitant use of COCs with lamotrigine may significantly decrease systemic exposure of lamotrigine due to induction of lamotrigine glucuronidation. Decreased systemic exposure of lamotrigine may reduce seizure control. Prevention or management Dose adjustment may be necessary. Consult the approved product labeling for lamotrigine. Thyroid Hormone Replacement Therapy or Corticosteroid Replacement Therapy Clinical effect Concomitant use of COCs with thyroid hormone replacement therapy or corticosteroid replacement therapy may increase systemic exposure of thyroid-binding and cortisol-binding globulin [see Warnings and Precautions ( 5.12 )] . Prevention or management The dose of replacement thyroid hormone or cortisol therapy may need to be increased. Consult the approved product labeling for the therapy in use [see Warnings and Precautions ( 5.12 )] . Other Drugs Clinical effect Concomitant use of COCs may decrease systemic exposure of acetaminophen, morphine, salicylic acid, and temazepam. Concomitant use with ethinyl estradiol-containing COCs may increase systemic exposure of other drugs (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole). Prevention or management The dosage of drugs that can be affected by this interaction may need to be increased. Consult the approved product labeling for the concomitantly used drug. 7.3 Concomitant Use with Hepatitis C Virus (HCV) Combination Therapy – Liver Enzyme Elevation Do not co-administer RIVELSA with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Warnings and Precautions ( 5.4 )] , and glecaprevir/pibrentasvir due to potential for ALT elevations . 7.4 Effect on Laboratory Tests The use of COCs may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.
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