NuvaRing (etonogestrel/ethinyl estradiol vaginal ring) is a non-biodegradable, flexible, transparent, colorless to almost colorless, combination contraceptive vaginal ring containing two active components, a progestin, etonogestrel (13-ethyl-17-hydroxy-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-3-one) and an estrogen, ethinyl estradiol (19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol). When placed in the vagina, each ring releases on average 0.120 mg/day of etonogestrel and 0.015 mg/day of ethinyl estradiol over a three-week period of use. NuvaRing is made of ethylene vinylacetate copolymers (28% and 9% vinylacetate) and magnesium stearate and contains 11.7 mg etonogestrel and 2.7 mg ethinyl estradiol. NuvaRing is not made with natural rubber latex. NuvaRing has an outer diameter of 54 mm and a cross-sectional diameter of 4 mm. The molecular weights for etonogestrel and ethinyl estradiol are 324.46 and 296.40, respectively. The structural formulas are as follows: Chemical Structure

FOR VAGINAL USE ONLY NuvaRing ® is indicated for use by females of reproductive age to prevent pregnancy. NuvaRing is an estrogen/progestin combination hormonal contraceptive (CHC) indicated for use by women to prevent pregnancy.

NuvaRing (etonogestrel/ethinyl estradiol vaginal ring) is a non-biodegradable, flexible, transparent, colorless to almost colorless, combination contraceptive vaginal ring, with an outer diameter of 54 mm and a cross-sectional diameter of 4 mm. It is made of ethylene vinylacetate copolymers and magnesium stearate, and contains 11.7 mg etonogestrel and 2.7 mg ethinyl estradiol. When placed in the vagina, each ring releases on average 0.120 mg/day of etonogestrel and 0.015 mg/day of ethinyl estradiol over a three-week period of use. NuvaRing is not made with natural rubber latex. NuvaRing is a polymeric vaginal ring containing 11.7 mg etonogestrel and 2.7 mg ethinyl estradiol, which releases on average 0.12 mg/day of etonogestrel and 0.015 mg/day of ethinyl estradiol.

One NuvaRing is inserted in the vagina. The ring must remain in place continuously for three weeks, followed by a one-week ring-free interval

How to Use NuvaRing To achieve maximum contraceptive effectiveness, NuvaRing must be used as directed . One NuvaRing is inserted in the vagina. The ring is to remain in place continuously for three weeks. It is removed for a one-week break, during which a withdrawal bleed usually occurs. A new ring is inserted one week after the last ring was removed. The user can choose the insertion position that is most comfortable to her, for example, standing with one leg up, squatting, or lying down. The ring is to be compressed and inserted into the vagina. The exact position of NuvaRing inside the vagina is not critical for its function. The vaginal ring must be inserted on the appropriate day and left in place for three consecutive weeks. This means that the ring should be removed three weeks later on the same day of the week as it was inserted and at about the same time. NuvaRing can be removed by hooking the index finger under the forward rim or by grasping the rim between the index and middle finger and pulling it out. The used ring should be placed in the sachet (foil pouch) and discarded in a waste receptacle out of the reach of children and pets (do not flush in toilet). After a one-week break, during which a withdrawal bleed usually occurs, a new ring is inserted on the same day of the week as it was inserted in the previous cycle. The withdrawal bleed usually starts on Day 2-3 after removal of the ring and may not have finished before the next ring is inserted. In order to maintain contraceptive effectiveness, the new ring must be inserted exactly one week after the previous one was removed even if menstrual bleeding has not finished

How to Start Using NuvaRing IMPORTANT: Consider the possibility of ovulation and conception prior to the first use of NuvaRing . No Hormonal Contraceptive Use in the Preceding Cycle: The woman should insert NuvaRing on the first day of her menstrual bleeding. NuvaRing may also be started on Days 2-5 of the woman's cycle, but in this case a barrier method, such as male condoms with spermicide, should be used for the first seven days of NuvaRing use in the first cycle. Changing From a CHC: The woman may switch from her previous CHC on any day, but at the latest on the day following the usual hormone-free interval, if she has been using her hormonal method consistently and correctly, or if it is reasonably certain that she is not pregnant. Changing From a Progestin-Only Method (progestin-only pill [POP], Implant, or Injection or a Progestin-Releasing Intrauterine System [IUS]): The woman may switch from the POP on any day; instruct her to start using NuvaRing on the day after she took her last POP. She should switch from an implant or the IUS on the day of its removal, and from an injectable on the day when the next injection would be due. In all of these cases, the woman should use an additional barrier method such as a male condom with spermicide, for the first seven days. Use After Abortion or Miscarriage: The woman may start using NuvaRing within the first five days following a complete first trimester abortion or miscarriage, and she does not need to use an additional method of contraception. If use of NuvaRing is not started within five days following a first trimester abortion or miscarriage, the woman should follow the instructions for "No Hormonal Contraceptive Use in the Preceding Cycle." In the meantime, she should be advised to use a non-hormonal contraceptive method. Start NuvaRing no earlier than four weeks after a second trimester abortion or miscarriage, due to the increased risk of thromboembolism. Following Childbirth: The use of NuvaRing may be initiated no sooner than four weeks postpartum in women who elect not to breastfeed, due to the increased risk of thromboembolism in the postpartum period. Advise women who are breastfeeding not to use NuvaRing but to use other forms of contraception until the child is weaned. If a woman begins using NuvaRing postpartum, instruct her to use an additional method of contraception, such as male condoms with spermicide, for the first seven days. If she has not yet had a period, consider the possibility of ovulation and conception occurring prior to initiation of NuvaRing

Deviations from the Recommended Regimen To prevent loss of contraceptive efficacy, advise women not to deviate from the recommended regimen. NuvaRing should be left in the vagina for a continuous period of three weeks. Advise women to regularly check for the presence of NuvaRing in the vagina (for example, before and after intercourse). Inadvertent Removal or Expulsion: NuvaRing can be accidentally expelled, for example, while removing a tampon, during intercourse, or with straining during a bowel movement. NuvaRing should be left in the vagina for a continuous period of three weeks. If the ring is accidentally expelled and is left outside of the vagina for less than three hours , contraceptive efficacy is not reduced. NuvaRing can be rinsed with cool to lukewarm (not hot) water and reinserted as soon as possible, but at the latest within three hours. If NuvaRing is lost, a new vaginal ring should be inserted and the regimen should be continued without alteration. If NuvaRing is out of the vagina for more than three continuous hours: During Weeks 1 and 2: Contraceptive efficacy may be reduced. The woman should reinsert the ring as soon as she remembers. A barrier method such as male condoms with spermicides must be used until the ring has been used continuously for seven days. During Week 3: The woman should discard that ring. One of the following two options should be chosen: Insert a new ring immediately. Inserting a new ring will start the next three-week use period. The woman may not experience a withdrawal bleed from her previous cycle. However, breakthrough spotting or bleeding may occur. Insert a new ring no later than seven days from the time the previous ring was removed or expelled, during which time she may have a withdrawal bleed. This option should only be chosen if the ring was used continuously for at least seven days prior to inadvertent removal/expulsion. In either case, a barrier method such as male condoms with spermicides must be used until the new ring has been used continuously for seven days. If NuvaRing was out of the vagina for an unknown amount of time, the possibility of pregnancy should be considered. A pregnancy test should be performed prior to inserting a new ring. Prolonged Ring-Free Interval: If the ring-free interval has been extended beyond one week, consider the possibility of pregnancy, and an additional method of contraception, such as male condoms with spermicide, MUST be used until NuvaRing has been used continuously for seven days. Prolonged Use of NuvaRing: If NuvaRing has been left in place for up to one extra week (i.e., up to four weeks total), the woman will remain protected. NuvaRing should be removed and the woman should insert a new ring after a one-week ring-free interval. If NuvaRing has been left in place for longer than four weeks, instruct the woman to remove the ring, and rule out pregnancy. If pregnancy is ruled out, NuvaRing may be restarted, and an additional method of contraception, such as male condoms with spermicide, MUST be used until a new NuvaRing has been used continuously for seven days. Ring Breakage: There have been reported cases of NuvaRing disconnecting at the weld joint. This is not expected to affect the contraceptive effectiveness of NuvaRing. In the event of a disconnected ring, vaginal discomfort or expulsion (slipping out) is more likely to occur. Vaginal injury associated with ring breakage has been reported . If a woman discovers that her NuvaRing has disconnected, she should discard the ring and replace it with a new ring

In the Event of a Missed Menstrual Period If the woman has not adhered to the prescribed regimen (NuvaRing has been out of the vagina for more than three hours or the preceding ring-free interval was extended beyond one week), consider the possibility of pregnancy at the time of the first missed period and discontinue NuvaRing use if pregnancy is confirmed. If the woman has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. If the woman has retained one NuvaRing for longer than four weeks, rule out pregnancy

Use with Other Vaginal Products NuvaRing may interfere with the correct placement and position of certain female barrier methods such as a diaphragm, cervical cap or female condom. These methods are not recommended as back-up methods with NuvaRing use. Pharmacokinetic data show that the use of tampons has no effect on the systemic absorption of the hormones released by NuvaRing.

Vascular risks: Stop NuvaRing use if a thrombotic event occurs. Stop NuvaRing use 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. Toxic Shock Syndrome (TSS): If patient exhibits signs or symptoms of TSS, consider the possibility of this diagnosis and initiate appropriate medical evaluation and treatment. Liver disease: Discontinue NuvaRing use if jaundice develops. High blood pressure: If used in women with well-controlled hypertension, monitor blood pressure and stop NuvaRing use if blood pressure rises significantly. Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. Headache: Evaluate significant change in headaches and discontinue NuvaRing use if indicated. Uterine bleeding: Evaluate irregular bleeding or amenorrhea. 5.1 Thromboembolic Disorders and Other Vascular Problems Stop NuvaRing use if an arterial thrombotic or venous thromboembolic event (VTE) occurs. Stop NuvaRing use if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. If feasible, stop NuvaRing at least four weeks before and through two weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism, and during and following prolonged immobilization. Start NuvaRing no earlier than 4 weeks after delivery, in women 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. The use of CHCs increases the risk of VTE. Known risk factors for VTE include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of CHCs . Two epidemiologic studies 1, 2, 3 that assessed the risk of VTE associated with the use of NuvaRing are described below. In these studies, which were required or sponsored by regulatory agencies, NuvaRing users had a risk of VTE similar to Combined Oral Contraceptives (COCs) users . A large prospective, observational study, the Transatlantic Active Surveillance on Cardiovascular Safety of NuvaRing (TASC), investigated the risk of VTE for new users, and women who were switching to or restarting NuvaRing or COCs in a population that is representative of routine clinical users. The women were followed for 24 to 48 months. The results showed a similar risk of VTE among NuvaRing users (VTE incidence 8.3 per 10,000 WY) and women using COCs (VTE incidence 9.2 per 10,000 WY). For women using COCs that did not contain the progestins desogestrel (DSG) or gestodene (GSD), VTE incidence was 8.9 per 10,000 WY. A retrospective cohort study using data from 4 health plans in the US (FDA-funded Study in Kaiser Permanente and Medicaid databases) showed the VTE incidence for new users of NuvaRing to be 11.4 events per 10,000 WY, for new users of a levonorgestrel (LNG)-containing COC 9.2 events per 10,000 WY, and for users of other COCs available during the course of the study Includes low-dose COCs containing the following progestins: norgestimate, norethindrone, or levonorgestrel

events per 10,000 WY. Table 1: Estimates (Hazard Ratios) of Venous Thromboembolism Risk in Users of NuvaRing Compared to Users of Combined Oral Contraceptives (COCs) Epidemiologic Study (Author, Year of Publication) Population Studied Comparator Product(s) Hazard Ratios (HR) (95% CI) TASC (Dinger, 2012) Initiators, including new users, switchers and restarters All COCs available during the course of the study Includes low-dose COCs containing the following progestins: chlormadinone acetate, cyproterone acetate, desogestrel, dienogest, drospirenone, ethynodiol diacetate, gestodene, levonorgestrel, norethindrone, norgestimate, or norgestrel COCs available excluding DSG- or GSD -containing OCs HR Adjusted for age, BMI, duration of use, VTE history : 0.8 (0.5-1.5) HR : 0.8 (0.4-1.7) FDA-funded Study in Kaiser Permanente and Medicaid databases (Sidney, 2011) First use of a combined hormonal contraceptive (CHC) during the study period COCs available during the course of the study Includes low-dose COCs containing the following progestins: norgestimate, norethindrone, or levonorgestrel HR Adjusted for age, site, year of entry into study : 1.1 (0.6-2.2) LNG/0.03 mg ethinyl estradiol HR : 1.0 (0.5-2.0) An increased risk of thromboembolic and thrombotic disease associated with the use of CHCs is well-established. Although the absolute VTE rates are increased for users of CHCs compared to non-users, the rates associated with pregnancy are even greater, especially during the post-partum period . The frequency of VTE in women using CHCs has been estimated to be 3 to 12 cases per 10,000 women-years. The risk of VTE is highest during the first year of CHC use and after restarting a CHC following a break of at least four weeks. The risk of VTE due to CHCs gradually disappears after use is discontinued. Figure 1 shows the risk of developing a VTE for women who are not pregnant and do not use CHCs, for women who use CHCs, for pregnant women, and for women in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 women who are not pregnant and do not use CHCs are followed for one year, between 1 and 5 of these women will develop a VTE. Figure 1: Likelihood of Developing a VTE *CHC=combination hormonal contraception **Pregnancy data based on actual duration of pregnancy in the reference studies. Based on a model assumption that pregnancy duration is nine months, the rate is 7 to 27 per 10,000 WY. Several epidemiology studies indicate that third generation oral contraceptives, including those containing desogestrel (etonogestrel, the progestin in NuvaRing, is the biologically active metabolite of desogestrel), may be associated with a higher risk of VTE than oral contraceptives containing other progestins. Some of these studies indicate an approximate two-fold increased risk. However, data from other studies have not shown this two-fold increase in risk. Use of CHCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. CHCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes). In general, the risk is greatest among older (>35 years of age), hypertensive women who also smoke. Use NuvaRing with caution in women with cardiovascular disease risk factors. Figure 1 5.2 Toxic Shock Syndrome (TSS) Cases of TSS have been reported by NuvaRing users. TSS has been associated with tampons and certain barrier contraceptives, and, in some cases the NuvaRing users were also using tampons. A causal relationship between the use of NuvaRing and TSS has not been established. If a patient exhibits signs or symptoms of TSS, consider the possibility of this diagnosis and initiate appropriate medical evaluation and treatment

Liver Disease Impaired Liver Function Do not use NuvaRing in women with liver disease such as acute viral hepatitis or severe (decompensated) cirrhosis of the liver . Acute or chronic disturbances of liver function may necessitate the discontinuation of CHC use until markers of liver function return to normal and CHC causation has been excluded . Discontinue NuvaRing use if jaundice develops. Liver Tumors NuvaRing is contraindicated in women with benign and malignant liver tumors . Hepatic adenomas are associated with CHC use. An estimate of the attributable risk is 3.3 cases per 100,000 CHC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long term (>8 years) CHC users. However, the attributable risk of liver cancers in CHC users is less than one case per million users

Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment CHCs, such as NuvaRing, are contraindicated for use with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir (with or without dasabuvir) . Discontinue NuvaRing prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir (with or without dasabuvir). NuvaRing can be restarted approximately 2 weeks following completion of treatment with this hepatitis C combination drug regimen. During clinical trials with some HCV combination drug regimens, ALT elevations were observed in women using ethinyl estradiol containing medications . For example, the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with and 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 CHCs

High Blood Pressure NuvaRing is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease . For women with well-controlled hypertension, monitor blood pressure and stop NuvaRing use if blood pressure rises significantly. An increase in blood pressure has been reported in women using CHCs and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentrations of progestin

Hypersensitivity Reactions Hypersensitivity reactions of anaphylaxis and angioedema have been reported during use of NuvaRing. If anaphylaxis and/or angioedema is suspected, NuvaRing should be discontinued and appropriate treatment administered. 5.7 Vaginal Use NuvaRing may not be suitable for women with conditions that make the vagina more susceptible to vaginal irritation or ulceration. Vaginal/cervical erosion or ulceration in women using NuvaRing has been reported. In some cases, the ring adhered to vaginal tissue, necessitating removal by a healthcare provider and in some instances (i.e., when the tissue had grown over the ring), removal was achieved by cutting the ring without incising the overlying vaginal tissue. Some women are aware of the ring on occasion during the 21 days of use or during intercourse, and sexual partners may feel NuvaRing in the vagina

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

Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who are using NuvaRing. CHCs may decrease glucose tolerance. Consider alternative contraception for women with uncontrolled dyslipidemia. Some women will have adverse lipid changes while on CHCs. Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using CHCs

Headache If a woman using NuvaRing develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue NuvaRing if indicated. Consider discontinuation of NuvaRing in the case of an increased frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event)

Bleeding Irregularities and Amenorrhea Unscheduled Bleeding and Spotting Unscheduled bleeding (breakthrough or intracyclic) bleeding and spotting sometimes occur in women using CHCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, 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 CHC. Bleeding patterns were evaluated in three large clinical studies. In the North American study (US and Canada, N=1,177), the percentages of subjects with breakthrough bleeding/spotting ranged from 7.2% to 11.7% during cycles 1-13. In the two non-US studies, the percentages of subjects with breakthrough bleeding/spotting ranged from 2.6% to 6.4% (Europe, N=1,145) and from 2.0% to 8.7% (Europe, Brazil, Chile, N=512). Amenorrhea and Oligomenorrhea If scheduled (withdrawal) bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule, consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. Occasional missed periods may occur with the appropriate use of NuvaRing. In the clinical studies, the percent of women who did not have withdrawal bleeding in a given cycle ranged from 0.3% to 3.8%. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. Some women may experience amenorrhea or oligomenorrhea after discontinuing CHC use, especially when such a condition was pre-existent

Inadvertent Urinary Bladder Insertion There have been reports of inadvertent insertions of NuvaRing into the urinary bladder, which required cystoscopic removal. Assess for ring insertion into the urinary bladder in NuvaRing users who present with persistent urinary symptoms and are unable to locate the ring

Depression Carefully observe women with a history of depression and discontinue NuvaRing use if depression recurs to a serious degree

Malignant Neoplasms Breast Cancer NuvaRing is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive . 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 . Cervical Cancer Some studies suggest that CHCs 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 may be due to differences in sexual behavior and other factors

Effect on Binding Globulins The estrogen component of CHCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. The dose of replacement thyroid hormones or cortisol therapy may need to be increased

Monitoring A woman who is using NuvaRing should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare

Hereditary Angioedema In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema

Chloasma Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while using NuvaRing.

Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. Drugs or herbal products that induce certain enzymes, such as CYP3A4, may decrease the effectiveness of CHCs or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with CHCs

Effects of Other Drugs on CHCs Substances decreasing the plasma concentrations of CHCs and potentially diminishing the effectiveness of CHCs Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of CHCs and potentially diminish the effectiveness of CHCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include: phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John's wort. Interactions between CHCs and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative non-hormonal method of contraception or a back-up method when enzyme inducers are used with NuvaRing, and to continue back-up non-hormonal contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. Note: NuvaRing may interfere with the correct placement and position of certain female barrier methods such as a diaphragm or female condom. These methods are not recommended as back-up methods with NuvaRing use . The serum concentrations of etonogestrel and ethinyl estradiol were not affected by concomitant administration of oral amoxicillin or doxycycline in standard dosages during 10 days of antibiotic treatment. The effects of other antibiotics on etonogestrel or ethinyl estradiol concentrations have not been evaluated. Substances increasing the plasma concentrations of CHCs Co-administration of atorvastatin and certain CHCs containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20-25%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. Concomitant administration of strong or moderate CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma estrogen and/or progestin concentrations. Co-administration of vaginal miconazole nitrate and NuvaRing increases the serum concentrations of etonogestrel and ethinyl estradiol by up to 40% . Human immunodeficiency virus (HIV) / Hepatitis C Virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors Significant changes in the plasma concentrations of the estrogen and /or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir]) /HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., efavirenz, nevirapine] or increase [e.g., etravirine]). These changes may be clinically relevant in some cases

Effects of CHCs on Other Drugs CHCs containing ethinyl estradiol may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. CHCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid and temazepam. A significant decrease in the plasma concentrations of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increase with use of CHCs

Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer NuvaRing with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations. Concomitant use with some other HCV antiviral medicinal products, such as those containing glecaprevir/pibrentasvir, may increase the risk of ALT elevations

Interference with Laboratory Tests The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.