Etonogestrel and Ethinyl Estradiol Vaginal

6 ADVERSE REACTIONS The following serious adverse reactions with the use of CHCs are discussed elsewhere in the labeling. Serious cardiovascular events and stroke [ see Boxed Warning and Warnings and Precautions ( 5.1 ) ] Vascular events [ see Warnings and Precautions ( 5.1 ) ] Liver disease [ see Warnings and Precautions ( 5.3 ) ] Adverse reactions commonly reported by CHC users are: Irregular uterine bleeding Nausea Breast tenderness Headache The most common adverse reactions (≥2%) in clinical trials were: vaginitis, headache (including migraine), mood changes (e.g., depression, mood swings, mood altered, depressed mood, affect lability), device-related events (e.g., expulsion/discomfort/foreign body sensation), nausea/vomiting, vaginal discharge, increased weight, vaginal discomfort, breast pain/discomfort/tenderness, dysmenorrhea, abdominal pain, acne, and decreased libido. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials 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 rates in the clinical trials of another drug and may not reflect the rates observed in practice. Trials with a duration of 6 to 13 28-day cycles provided safety data. In total, 2,501 women, aged 18 to 41 contributed 24,520 cycles of exposure. Common Adverse Reactions (≥ 2%): vaginitis (13.8%), headache (including migraine) (11.2%), mood changes (e.g., depression, mood swings, mood altered, depressed mood, affect lability) (6.4%), device-related events (e.g., expulsion/discomfort/foreign body sensation) (6.3%), nausea/vomiting (5.9%), vaginal discharge (5.7%), increased weight (4.9%), vaginal discomfort (4.0%), breast pain/discomfort/tenderness (3.8%), dysmenorrhea (3.5%), abdominal pain (3.2%), acne (2.4%), and decreased libido (2.0%). Adverse Reactions (≥ 1%) Leading to Study Discontinuation: 13.0% of the women discontinued from the clinical trials due to an adverse reaction; the most common adverse reactions leading to discontinuation were device-related events (2.7%), mood changes (1.7%), headache (including migraine) (1.5%) and vaginal symptoms (1.2%). Serious Adverse Reactions: deep vein thrombosis [ see Warnings and Precautions ( 5.1 ) ], anxiety, cholelithiasis, and vomiting. 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 2). 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 2: 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 Etonogestrel and ethinyl estradiol vaginal ring. 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. Immune system disorders : hypersensitivity reactions, including anaphylaxis and angioedema Nervous system disorders : stroke/cerebrovascular accident Vascular disorders : arterial events (including arterial thromboembolism and myocardial infarction), aggravation of varicose veins Skin and subcutaneous tissue disorders : urticaria, chloasma Reproductive system and breast disorders : penile disorders, including local reactions on penis (in male partners of women using Etonogestrel and ethinyl estradiol vaginal ring), galactorrhea General Disorders and Administration Site Conditions : device breakage (including with concomitant use of intravaginal antimycotic, antibiotic, and lubricant products) Injury, poisoning and procedural complications : vaginal injury (including associated pain, discomfort, and bleeding) associated with ring breakage enilloring-chart

4 CONTRAINDICATIONS Etonogestrel and ethinyl estradiol vaginal ring 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 women who are known to: Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions ( 5.1 )] Have deep vein thrombosis or pulmonary embolism, now or in the past [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 [see Warnings and Precautions ( 5.5 )] Have diabetes mellitus with vascular disease [see Warnings and Precautions ( 5.9 )] Have headaches with focal neurological symptoms or migraine headaches with aura [see Warnings and Precautions ( 5.10 )] Women over age 35 with any migraine headaches [see Warnings and Precautions ( 5.10 )] Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions ( 5.3 )and Use in Specific Populations ( 8.6 )] Undiagnosed abnormal uterine bleeding [see Warnings and Precautions ( 5.11 )] Pregnancy, because there is no reason to use CHCs during pregnancy [see Use in Specific Populations ( 8.1 )] Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [see Warnings and Precautions ( 5.14 )] Hypersensitivity reactions, including anaphylaxis and angioedema, to any of the components of Etonogestrel and ethinyl estradiol vaginal ring [see Warnings and Precautions ( 5.6 ) and Adverse Reactions ( 6 )] Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions ( 5.4 )]. A high risk of arterial or venous thrombotic diseases ( 4 ) Breast cancer ( 4 ) Liver tumors or liver disease ( 4 ) Undiagnosed abnormal uterine bleeding ( 4 ) Pregnancy ( 4 ) Hypersensitivity, including anaphylaxis and angioedema, to any of the components of Etonogestrel and ethinyl estradiol vaginal ring ( 4 ) Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4 )

11 DESCRIPTION Etonogestrel and 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. Etonogestrel and ethinyl estradiol vaginal ring 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. Etonogestrel and ethinyl estradiol vaginal ring is not made with natural rubber latex. Etonogestrel and ethinyl estradiol vaginal ring 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: structure

2 DOSAGE AND ADMINISTRATION One Etonogestrel and ethinyl estradiol vaginal ring is inserted in the vagina. The ring must remain in place continuously for three weeks, followed by a one-week ring-free interval. ( 2 ) 2.1 How to Use Etonogestrel and ethinyl estradiol vaginal ring To achieve maximum contraceptive effectiveness, Etonogestrel and ethinyl estradiol vaginal ring must be used as directed [ see Dosage and Administration ( 2.2 )]. One Etonogestrel and ethinyl estradiol vaginal ring 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. An optional alternative is to insert the ring using the applicator for Etonogestrel and ethinyl estradiol vaginal ring [see Applicator for Etonogestrel and ethinyl estradiol vaginal ring Instructions for Use ]. The exact position of Etonogestrel and ethinyl estradiol vaginal ring 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. Etonogestrel and ethinyl estradiol vaginal ring 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. 2.2 How to Start Using Etonogestrel and ethinyl estradiol vaginal ring IMPORTANT: Consider the possibility of ovulation and conception prior to the first use of Etonogestrel and ethinyl estradiol vaginal ring. No Hormonal Contraceptive Use in the Preceding Cycle: The woman should insert Etonogestrel and ethinyl estradiol vaginal ring on the first day of her menstrual bleeding. Etonogestrel and ethinyl estradiol vaginal ring 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 Etonogestrel and ethinyl estradiol vaginal ring 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 Etonogestrel and ethinyl estradiol vaginal ring 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 Etonogestrel and ethinyl estradiol vaginal ring 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 Etonogestrel and ethinyl estradiol vaginal ring 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 Etonogestrel and ethinyl estradiol vaginal ring no earlier than four weeks after a second trimester abortion or miscarriage, due to the increased risk of thromboembolism. [ See Contraindications ( 4 ) and Warnings and Precautions ( 5.1 ) .] Following Childbirth: The use of Etonogestrel and ethinyl estradiol vaginal ring 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. [See Contraindications ( 4 ) and Warnings and Precautions ( 5.1 ).] Advise women who are breastfeeding not to use Etonogestrel and ethinyl estradiol vaginal ring but to use other forms of contraception until the child is weaned. If a woman begins using Etonogestrel and ethinyl estradiol vaginal ring 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 Etonogestrel and ethinyl estradiol vaginal ring. 2.3 Deviations from the Recommended Regimen To prevent loss of contraceptive efficacy, advise women not to deviate from the recommended regimen. Etonogestrel and ethinyl estradiol vaginal ring should be left in the vagina for a continuous period of three weeks. Advise women to regularly check for the presence of Etonogestrel and ethinyl estradiol vaginal ring in the vagina (for example, before and after intercourse). Inadvertent Removal or Expulsion: Etonogestrel and ethinyl estradiol vaginal ring can be accidentally expelled, for example, while removing a tampon, during intercourse, or with straining during a bowel movement. Etonogestrel and ethinyl estradiol vaginal ring 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. Etonogestrel and ethinyl estradiol vaginal ring can be rinsed with cool to lukewarm (not hot) water and reinserted as soon as possible , but at the latest within three hours. If Etonogestrel and ethinyl estradiol vaginal ring is lost, a new vaginal ring should be inserted and the regimen should be continued without alteration. If Etonogestrel and ethinyl estradiol vaginal ring 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: 1. 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. 2. 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 Etonogestrel and ethinyl estradiol vaginal ring 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 Etonogestrel and ethinyl estradiol vaginal ring has been used continuously for seven days. Prolonged Use of Etonogestrel and ethinyl estradiol vaginal ring: If Etonogestrel and ethinyl estradiol vaginal ring has been left in place for up to one extra week (i.e., up to four weeks total), the woman will remain protected. Etonogestrel and ethinyl estradiol vaginal ring should be removed and the woman should insert a new ring after a one-week ring-free interval. If Etonogestrel and ethinyl estradiol vaginal ring 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, Etonogestrel and ethinyl estradiol vaginal ring may be restarted, and an additional method of contraception, such as male condoms with spermicide, MUST be used until a new Etonogestrel and ethinyl estradiol vaginal ring has been used continuously for seven days. Ring Breakage: There have been reported cases of Etonogestrel and ethinyl estradiol vaginal ring disconnecting at the weld joint. This is not expected to affect the contraceptive effectiveness of Etonogestrel and ethinyl estradiol vaginal ring. 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 [see Adverse Reactions ( 6.2 )] . If a woman discovers that her Etonogestrel and ethinyl estradiol vaginal ring has disconnected, she should discard the ring and replace it with a new ring. 2.4 In the Event of a Missed Menstrual Period 1. If the woman has not adhered to the prescribed regimen (Etonogestrel and ethinyl estradiol vaginal ring 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 Etonogestrel and ethinyl estradiol vaginal ring use if pregnancy is confirmed. 2. If the woman has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. 3. If the woman has retained one Etonogestrel and ethinyl estradiol vaginal ring for longer than four weeks, rule out pregnancy. 2.5 Use with Other Vaginal Products Etonogestrel and ethinyl estradiol vaginal ring 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 Etonogestrel and ethinyl estradiol vaginal ring use. Pharmacokinetic data show that the use of tampons has no effect on the systemic absorption of the hormones released by Etonogestrel and ethinyl estradiol vaginal ring .

1 INDICATIONS AND USAGE FOR VAGINAL USE ONLY Etonogestrel and ethinyl estradiol vaginal ring is indicated for use by females of reproductive age to prevent pregnancy. Etonogestrel and ethinyl estradiol vaginal ring is an estrogen/progestin combination hormonal contraceptive (CHC) indicated for use by women to prevent pregnancy. ( 1 )

10 OVERDOSAGE There have been no reports of serious ill effects from overdose of CHCs. Overdosage may cause withdrawal bleeding in females and nausea. If the ring breaks, it does not release a higher dose of hormones. In case of suspected overdose, all Etonogestrel and ethinyl estradiol vaginal ring should be removed and symptomatic treatment given.

7 DRUG INTERACTIONS 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. ( 7 ) 7.1 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 Etonogestrel and ethinyl estradiol vaginal ring, and to continue back-up non-hormonal contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. Note: Etonogestrel and ethinyl estradiol vaginal ring 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 Etonogestrel and ethinyl estradiol vaginal ring use [see Dosage and Administration ( 2.5 )] . 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 Etonogestrel and ethinyl estradiol vaginal ring increases the serum concentrations of etonogestrel and ethinyl estradiol by up to 40% [see Clinical Pharmacology ( 12.3 )]. Human immunodeficiency virus (HIV) / Hepatitis C Virus (HCV) protease inhibitors and nonnucleoside 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. 7.2 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. 7.3 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer Etonogestrel and ethinyl estradiol vaginal ring with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [ see Warnings and Precautions ( 5.4 ) ]. 7.4 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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Combination hormonal contraceptives act by suppression of gonadotropins. Although the primary effect of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation). 12.3 Pharmacokinetics Absorption Etonogestrel : Etonogestrel released by Etonogestrel and ethinyl estradiol vaginal ring is rapidly absorbed. The bioavailability of etonogestrel after vaginal administration is approximately 100%. The serum etonogestrel and ethinyl estradiol concentrations observed during three weeks of Etonogestrel and ethinyl estradiol vaginal ring use are summarized in Table 2. Ethinyl estradiol: Ethinyl estradiol released by Etonogestrel and ethinyl estradiol vaginal ring is rapidly absorbed. The bioavailability of ethinyl estradiol after vaginal administration is approximately 56%, which is comparable to that with oral administration of ethinyl estradiol. The serum ethinyl estradiol concentrations observed during three weeks of Etonogestrel and ethinyl estradiol vaginal ring use are summarized in Table 2. Table 2: Mean (SD) Serum Etonogestrel and Ethinyl Estradiol Concentrations (n=16) 1 week 2 weeks 3 weeks etonogestrel (pg/mL) 1578 (408) 1476 (362) 1374 (328) ethinyl estradiol (pg/mL) 19.1 (4.5) 18.3 (4.3) 17.6 (4.3) The pharmacokinetic profile of etonogestrel and ethinyl estradiol during use of Etonogestrel and ethinyl estradiol vaginal ring is shown in Figure 3. Figure 3: Mean Serum Concentration-Time Profile of Etonogestrel and Ethinyl Estradiol during Three Weeks of Use The pharmacokinetic parameters of etonogestrel and ethinyl estradiol were determined during one cycle of Etonogestrel and ethinyl estradiol vaginal ring use in 16 healthy female subjects and are summarized in Table 3. Table 3: Mean (SD) Pharmacokinetic Parameters of Etonogestrel and ethinyl estradiol vaginal ring (n=16) Hormone C max pg/mL T max hr t1/2 hr CL L/hr etonogestrel 1716 (445) 200.3 (69.6) 29.3 (6.1) 3.4 (0.8) ethinyl estradiol 34.7 (17.5) 59.3 (67.5) 44.7 (28.8) 34.8 (11.6) Cmax -maximum serum drug concentration Tmax -time at which maximum serum drug concentration occurs t1/2 -elimination half-life, calculated by 0.693/Kelim CL -apparent clearance Prolonged use of Etonogestrel and ethinyl estradiol vaginal ring: The mean serum etonogestrel concentration at the end of the fourth week of continuous use of Etonogestrel and ethinyl estradiol vaginal ring was 1272 ± 311 pg/mL compared to a mean concentration range of 1578 ± 408 to 1374 ± 328 pg/mL at the end of weeks one to three. The mean serum ethinyl estradiol concentration at the end of the fourth week of continuous use of Etonogestrel and ethinyl estradiol vaginal ring was 16.8 ± 4.6 pg/mL compared to a mean concentration range of 19.1 ± 4.5 to 17.6 ± 4.3 pg/mL at the end of weeks one to three. Distribution Etonogestrel: Etonogestrel is approximately 32% bound to sex hormone-binding globulin (SHBG) and approximately 66% bound to albumin in blood. Ethinyl estradiol: Ethinyl estradiol is highly but not specifically bound to serum albumin (98.5%) and induces an increase in the serum concentrations of SHBG. Metabolism In vitro data shows that both etonogestrel and ethinyl estradiol are metabolized in liver microsomes by the cytochrome P450 3A4 isoenzyme. Ethinyl estradiol is primarily metabolized by aromatic hydroxylation, but a wide variety of hydroxylated and methylated metabolites are formed. These are present as free metabolites and as sulfate and glucuronide conjugates. The hydroxylated ethinyl estradiol metabolites have weak estrogenic activity. The biological activity of etonogestrel metabolites is unknown. Excretion Etonogestrel and ethinyl estradiol are primarily eliminated in urine, bile and feces. Drug Interactions [ See also Drug Interactions ( 7 ) .] The drug interactions of Etonogestrel and ethinyl estradiol vaginal ring were evaluated in several studies. A single-dose vaginal administration of an oil-based 1200-mg miconazole nitrate capsule increased the serum concentrations of etonogestrel and ethinyl estradiol by approximately 17% and 16%, respectively. Following multiple doses of 200 mg miconazole nitrate by vaginal suppository or vaginal cream, the mean serum concentrations of etonogestrel and ethinyl estradiol increased by up to 40%. A single-dose vaginal administration of 100-mg water-based nonoxynol-9 spermicide gel did not affect the serum concentrations of etonogestrel or ethinyl estradiol. 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. Tampon Use The use of tampons had no effect on serum concentrations of etonogestrel and ethinyl estradiol during use of Etonogestrel and ethinyl estradiol vaginal ring [ see Dosage and Administration ( 2.5 ) ]. image description

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3 DOSAGE FORMS AND STRENGTHS Etonogestrel and 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. Etonogestrel and ethinyl estradiol vaginal ring is not made with natural rubber latex. Etonogestrel and ethinyl estradiol vaginal ring 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. ( 3 )

Etonogestrel and Ethinyl Estradiol Vaginal Etonogestrel and Ethinyl Estradiol Vaginal ETHYLENE-VINYL ACETATE COPOLYMER (28% VINYL ACETATE) ETHYLENE-VINYL ACETATE COPOLYMER (9% VINYLACETATE) MAGNESIUM STEARATE ETHINYL ESTRADIOL ETHINYL ESTRADIOL ETONOGESTREL ETONOGESTREL

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a 24-month carcinogenicity study in rats with subdermal implants releasing 10 and 20 mcg etonogestrel per day, (approximately 0.3 and 0.6 times the systemic steady-state exposure of women using vEtonogestrel and ethinyl estradiol vaginal ring), no drug-related carcinogenic potential was observed. Mutagenesis Etonogestrel was not genotoxic in the in vitro Ames/Salmonella reverse mutation assay, the chromosomal aberration assay in Chinese hamster ovary cells or in the in vivo mouse micronucleus test. Impairment of Fertility A fertility study was conducted with etonogestrel in rats at approximately 600 times the anticipated daily vaginal human dose (~0.002 mg/kg/day). Treatment did not have any adverse effect on resulting litter parameters after cessation of treatment supporting the return to fertility after suppression with etonogestrel.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a 24-month carcinogenicity study in rats with subdermal implants releasing 10 and 20 mcg etonogestrel per day, (approximately 0.3 and 0.6 times the systemic steady-state exposure of women using vEtonogestrel and ethinyl estradiol vaginal ring), no drug-related carcinogenic potential was observed. Mutagenesis Etonogestrel was not genotoxic in the in vitro Ames/Salmonella reverse mutation assay, the chromosomal aberration assay in Chinese hamster ovary cells or in the in vivo mouse micronucleus test. Impairment of Fertility A fertility study was conducted with etonogestrel in rats at approximately 600 times the anticipated daily vaginal human dose (~0.002 mg/kg/day). Treatment did not have any adverse effect on resulting litter parameters after cessation of treatment supporting the return to fertility after suppression with etonogestrel.

ANDA211157

Etonogestrel and Ethinyl Estradiol Vaginal

Etonogestrel and Ethinyl Estradiol Vaginal

42291-478

HUMAN PRESCRIPTION DRUG

VAGINAL

PACKAGE LABEL PRINCIPAL DISPLAY PANEL SECTION 3

RECENT MAJOR CHANGES Warnings and Precautions ( 5.14 ) 04/2022

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Counsel patients regarding the following: Increased risk of cardiovascular events Advise patients that cigarette smoking increases the risk of serious cardiovascular events from use of Etonogestrel and ethinyl estradiol vaginal ring, and women who are over 35 years old and smoke should not use Etonogestrel and ethinyl estradiol vaginal ring [ see Boxed Warning ]. Inform patients that the increased risk of VTE compared to non-users of CHCs is greatest after initially starting a CHC or restarting (following a 4-week or greater CHC-free interval) the same or a different CHC [ see Warnings and Precautions ( 5.1 ) ]. Use and administration Inform patients that Etonogestrel and ethinyl estradiol vaginal ring does not protect against HIV infection (AIDS) and other sexually transmitted infections. Advise patients on the proper usage of Etonogestrel and ethinyl estradiol vaginal ring and what to do if she does not comply with the labeled timing of insertion and removal [ see Dosage and Administration ( 2 ) ]. Advise patients to regularly check for the presence of Etonogestrel and ethinyl estradiol vaginal ring in the vagina (for example, before and after intercourse) [ see Dosage and Administration ( 2.3 ) ]. Pregnancy Inform patients that Etonogestrel and ethinyl estradiol vaginal ring is not to be used during pregnancy. If pregnancy is planned or occurs during treatment with Etonogestrel and ethinyl estradiol vaginal ring, instruct the patient to discontinue Etonogestrel and ethinyl estradiol vaginal ring use [ see Use in Specific Populations ( 8.1 ) ]. Use of additional contraception Inform patients that they need to use a barrier method of contraception when the ring is out for more than three continuous hours until Etonogestrel and ethinyl estradiol vaginal ring has been used continuously for at least seven days [ see Dosage and Administration ( 2.3 ) ]. Advise patients to use a back-up or alternative method of contraception when enzyme inducers are used with Etonogestrel and ethinyl estradiol vaginal ring [ see Drug Interactions ( 7.1 )]. Inform patients who start EnilloRing postpartum and have not yet had a normal period that they should use an additional non-hormonal method of contraception for the first seven days [ see Dosage and Administration ( 2.2 )]. Lactation Inform patients that CHCs may reduce breast milk production. This is less likely to occur if breastfeeding is well established [ see Use in Specific Populations ( 8.2 )]. Amenorrhea Inform patients that amenorrhea may occur. Rule out pregnancy in the event of amenorrhea if Etonogestrel and ethinyl estradiol vaginal ring has been out of the vagina for more than three consecutive hours, if the ring-free interval was extended beyond one week, if the woman has missed a period for two or more consecutive cycles, and if the ring has been retained for longer than four weeks [ see Warnings and Precautions ( 5.11 ) ]. Disposal Advise patients on the proper disposal of a used Etonogestrel and ethinyl estradiol vaginal ring [see How Supplied/Storage and Handling ( 16 ) ]. Manufactured For: AvKARE Pulaski, TN 38478 PI-478-00 Rev. 09/2023

14 CLINICAL STUDIES In three large one-year clinical trials enrolling 2,834 women aged 18-40 years, in North America, Europe, Brazil, and Chile, the racial distribution was 93% Caucasian, 5.0% Black, 0.8% Asian, and 1.2% Other. Women with BMI ≥ 30 kg/m2 were excluded from these studies. Based on pooled data from the three trials, 2,356 women aged < 35 years completed 23,515 evaluable cycles of Etonogestrel and ethinyl estradiol vaginal ring use (cycles in which no back-up contraception was used). The pooled pregnancy rate (Pearl Index) was 1.28 (95% CI [0.8, 1.9]) per 100 women-years of Etonogestrel and ethinyl estradiol vaginal ring use. In the US study, the Pearl Index was 2.02 (95% CI [1.1, 3.4]) per 100 women-years of Etonogestrel and ethinyl estradiol vaginal ring use. Study data indicate the return of ovulation and spontaneous menstrual cycles in most women within a month after discontinuation of Etonogestrel and ethinyl estradiol vaginal ring use.

15 REFERENCES 1. Dinger, J et. al., Cardiovascular risk associated with the use of an etonogestrel-containing vaginal ring. Obstetrics & Gynecology 2013; 122(4): 800-808. 2. Sidney, S. et. al., Recent combined hormonal contraceptives (CHCs) and the risk of thromboembolism and other cardiovascular events in new users. Contraception 2013; 87: 93–100. 3. Combined hormonal contraceptives (CHCs) and the risk of cardiovascular endpoints. Sidney, S. (primary author) http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf , accessed 23-Aug-2013.

8 USE IN SPECIFIC POPULATIONS Nursing mothers: Not recommended; can decrease milk production. ( 8.2 ) 8.1 Pregnancy Risk Summary Etonogestrel and ethinyl estradiol vaginal ring is contraindicated during pregnancy because there is no need for pregnancy prevention in a woman who is already pregnant. Epidemiologic studies and meta-analyses have not shown an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following maternal exposure to low dose CHCs prior to conception or during early pregnancy. No adverse developmental outcomes were observed in pregnant rats and rabbits with the administration of etonogestrel during organogenesis at doses approximately 300 times the anticipated daily vaginal human dose (~0.002 mg/kg/day). No adverse developmental outcomes were observed in pregnant rats and rabbits with the co-administration of the combination desogestrel/ethinyl estradiol during organogenesis at desogestrel/ethinyl estradiol doses at least 2/5 times, respectively, the anticipated daily vaginal human dose (~0.002 desogestrel/0.00025 ethinyl estradiol mg/kg/day). Discontinue Etonogestrel and ethinyl estradiol vaginal ring use if pregnancy is confirmed. Data Animal Data In rats and rabbits at dosages up to 300 times the anticipated dose, etonogestrel is neither embryotoxic nor teratogenic. Co-administration of a maternally toxic dose of desogestrel/ethinyl estradiol to pregnant rats was associated with embryolethality and wavy ribs at a desogestrel/ethinyl estradiol dose that was 40/130 times, respectively, the anticipated vaginal human dose (0.002 desogestrel/0.00025 ethinyl estradiol mg/kg/day). No adverse embryofetal effects were observed when the combination was administered to pregnant rats at a desogestrel/ethinyl estradiol dose that was 4/13 times, respectively, the anticipated vaginal human dose. When desogestrel/ethinyl estradiol was given to pregnant rabbits, preimplantation loss was observed at a desogestrel/ethinyl estradiol dose that was 3/10 times, respectively, the anticipated vaginal human dose. No adverse embryofetal effects were observed when the combination was administered to pregnant rabbits at a desogestrel/ethinyl estradiol dose that was 2/5 times the anticipated vaginal human dose. 8.2 Lactation Risk Summary Small amounts of contraceptive steroids and/or metabolites, including etonogestrel and ethinyl estradiol are transferred to human milk. Harmful effects have not been observed in breastfed infants exposed to CHCs through breast milk. CHCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. When possible, advise the nursing mother to use non-estrogen-containing contraception until she has completely weaned her child. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Etonogestrel and ethinyl estradiol vaginal ring and any potential adverse effects on the breastfed child from Etonogestrel and ethinyl estradiol vaginal ring or from the underlying maternal condition. 8.4 Pediatric Use Safety and efficacy of Etonogestrel and ethinyl estradiol vaginal ring have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated. 8.5 Geriatric Use Etonogestrel and ethinyl estradiol vaginal ring has not been studied in postmenopausal women and is not indicated in this population. 8.6 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of Etonogestrel and ethinyl estradiol vaginal ring has not been studied. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of CHC use until markers of liver function return to normal. [ See Contraindications ( 4 ) and Warnings and Precautions ( 5.3 ) .] 8.7 Renal Impairment The effect of renal impairment on the pharmacokinetics of Etonogestrel and ethinyl estradiol vaginal ring has not been studied.

16 HOW SUPPLIED/STORAGE AND HANDLING Each Etonogestrel and ethinyl estradiol vaginal ring is individually packaged in an aluminum laminate sachet consisting of three layers, from outside to inside: polyester, aluminum foil, and low-density polyethylene. The ring should be replaced in this foil pouch after use and discarded in a waste receptacle out of the reach of children and pets. It should not be flushed down the toilet. Box of 3 sachets NDC 42291-478-03 16.1 Storage Prior to dispensing to the user, store refrigerated 2-8°C (36-46°F). After dispensing to the user, Etonogestrel and ethinyl estradiol vaginal ring can be stored for up to 4 months at 25°C (77°F); excursions permitted between 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Avoid storing Etonogestrel and ethinyl estradiol vaginal ring in direct sunlight or at temperatures above 30°C (86°F). For the Dispenser: When Etonogestrel and ethinyl estradiol vaginal ring is dispensed to the user, place an expiration date on the label. The date should not exceed either 4 months from the date of dispensing or the expiration date, whichever comes first.

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive (CHC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, CHCs, including Etonogestrel and ethinyl estradiol vaginal ring, should not be used by women who are over 35 years of age and smoke. [ see Contraindications ( 4 )] WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS See full prescribing information for complete boxed warning. Women over 35 years old who smoke should not use Etonogestrel and ethinyl estradiol vaginal ring ( 4 ) Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive (CHC) use. ( 4 )