Jolessa

1 INDICATIONS AND USAGE JOLESSA ® is indicated for use by females of reproductive potential to prevent pregnancy. JOLESSA is a combination of levonorgestrel, a progestin, and ethinyl estradiol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy.

Take one tablet daily by mouth at the same time every day for 91 days. Take tablets in the order directed on the Extended-Cycle Tablet Dispenser.

2.1How to Start and Take

JOLESSA JOLESSA is dispensed in an Extended-Cycle Tablet Dispenser . JOLESSA should be started on a Sunday . For the first cycle of a Sunday Start regimen, an additional method of contraception should be used until after the first 7 consecutive days of administration. Table 1: Instructions for Administration of JOLESSA Starting JOLESSA in females with no current use of hormonal contraception (Sunday Start) Important: Consider the possibility of ovulation and conception prior to initiation of this product. Tablet Color: JOLESSA active tablets are pink (Day 1 to Day 84).

JOLESSA inactive tablets are white (Day 85 to Day 91). Sunday Start: For each 91-day course, take in the following order: Take the first pink tablet (0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol) on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, take the tablet on that day.

Due to the potential risk of becoming pregnant, use additional non-hormonal contraception (such as condoms or spermicide) for the first 7 days of treatment. Take subsequent pink tablets once daily at the same time each day for a total of 84 days. Take one white tablet (inert) daily for the following 7 days and at the same time of day that active tablets were taken.

A scheduled period should occur during the 7 days that the white tablets are taken. Begin the next and all subsequent 91-day courses of JOLESSA without interruption on the same day of the week (Sunday) on which the patient began her first dose. Follow the same schedule as the initial 91-day course: a pink tablet once a day for 84 days, and a white tablet once a day for 7 days.

If the patient does not immediately start her next pill pack, instruct her to protect herself from pregnancy by using a non-hormonal backup method of contraception until she has taken a pink tablet daily for 7 consecutive days. Switching from another contraceptive method to JOLESSA Start JOLESSA: Another oral contraceptive On the day when the new pack of the previous COC would have been started Transdermal patch On the day when the next application would have been scheduled. Vaginal ring On the day when the next insertion would have been scheduled.

Injection On the day when the next injection would have been scheduled. Intrauterine contraceptive (IUD) On the day of removal. If the IUD is not removed on first day of the patient’s menstrual cycle, additional non-hormonal contraception (such as condoms or spermicide) is needed for the first seven days of the first 91-day course.

Implant On the day of removal. Starting JOLESSA after Abortion or Miscarriage First-trimester After a first-trimester abortion or miscarriage, JOLESSA may be started immediately. An additional method of contraception is not needed if JOLESSA is started immediately. If JOLESSA is not started within 5 days after termination of the pregnancy, the patient should use additional non-hormonal contraception (such as condoms or spermicide) for the first seven days of her first 91-day course of JOLESSA. Second-trimester Do not start JOLESSA until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease.

Start JOLESSA following the instructions in Table 1 for Sunday start. Use additional non-hormonal contraception (such as condoms or spermicide) for the first seven days of the patient’s first 91-day course of JOLESSA . Starting JOLESSA after Childbirth Do not start JOLESSA until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with JOLESSA following the instructions in Table 1 for women not currently using hormonal contraception.

JOLESSA is not recommended for use in lactating women . If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of JOLESSA .

2.2Dosing

JOLESSA Instruct patients to take one tablet by mouth at the same time every day. The dosing of JOLESSA is one pink pill containing levonorgestrel and ethinyl estradiol daily for 84 consecutive days, followed by one white pill (inactive pills without hormone) for 7 days. To achieve maximum contraceptive effectiveness, JOLESSA must be taken exactly as directed, in the order directed on the Tablet Dispenser, and at intervals not exceeding 24 hours.

Start taking the first pink pill from a new Tablet Dispenser the very next day after taking the last white inactive pill in the Tablet Dispenser. The failure rate may increase when pills are missed or taken incorrectly.

2.3Missed Doses Table

2: Instructions for Missed JOLESSA Tablets If one active tablet (pink) is missed in Days 1 through 84 Take the tablet as soon as possible. Take the next tablet at the regular time and continue taking one tablet a day until the 91-day course is finished. If two consecutive active tablets (pink) are missed in Days 1 through 84 Take 2 tablets on the day remembered and 2 tablets the next day.

Then continue taking one tablet a day until the 91-day course is finished. Additional non-hormonal contraception (such as condoms or spermicide) should be used as backup if the patient has sex within 7 days after missing tablets. If three or more consecutive active tablets (pink) are missed in Days 1 through 84 Do not take the missed tablets.

Continue taking one tablet a day until the 91-day course is finished. Additional non-hormonal contraception (such as condoms or spermicide) must be used as backup if the patient has sex within 7 days after missing tablets. If any of the seven white (inactive) 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.

2.4Advice 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 pink tablet, handle this as a missed tablet.

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. Hypertension: If used in women with well-controlled hypertension, monitor blood pressure and stop if blood pressure rises significantly. Gallbladder disease: May cause or worsen gallbladder disease. Adverse carbohydrate and lipid effects: Monitor glucose in prediabetic and diabetic women taking JOLESSA. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. Headache: Evaluate significant change in headaches and discontinue if indicated. Uterine bleeding: May cause irregular bleeding or amenorrhea. Evaluate for other causes if symptoms persist.

5.1Thromboembolic Disorders and Other Vascular Conditions

Stop JOLESSA if an arterial or venous thrombotic/thromboembolic event occurs. Stop JOLESSA if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. Discontinue JOLESSA during prolonged immobilization.

If feasible, stop JOLESSA at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism. Start JOLESSA 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 likelihood of ovulation increases after the third postpartum week.

Before starting JOLESSA evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. JOLESSA is contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases . 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.

JOLESSA is contraindicated in women over 35 years of age who smoke . 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 . 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 . 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, for pregnant females 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 JOLESSA provides women with more hormonal exposure on a yearly basis than conventional monthly COCs containing the same strength synthetic estrogens and progestins (an additional 9 weeks of exposure per year). In the clinical trial, one case of pulmonary embolism was reported.

Postmarketing adverse reactions of VTE have been reported in women who used JOLESSA. Figure 1

5.2Liver Disease Elevated Liver Enzymes

JOLESSA is contraindicated in females with acute viral hepatitis or severe (decompensated) cirrhosis of the liver . Acute liver test abnormalities may necessitate the discontinuation of JOLESSA until the liver tests return to normal and JOLESSA causation has been excluded. Discontinue JOLESSA if jaundice develops. Liver Tumors JOLESSA is contraindicated in females with benign and malignant liver tumors . 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 through intra-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.

5.3Risk 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 JOLESSA. Discontinue JOLESSA prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir . JOLESSA can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

5.4Hypertension

JOLESSA is contraindicated in females with uncontrolled hypertension or hypertension with vascular disease . For all women, including those with well-controlled hypertension, monitor blood pressure at routine visits and stop JOLESSA if blood pressure rises significantly. An increase in blood pressure has been reported in females 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.

5.5Age-related Considerations The

risk for cardiovascular disease and prevalence of risk factors for cardiovascular disease increase 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 . Consider the presence of underlying risk factors that may increase the risk of cardiovascular disease or VTE, particularly before initiating JOLESSA for women over 35 years, such as: Hypertension Diabetes Dyslipidemia Obesity

5.6Gallbladder Disease Studies

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

5.7Adverse Carbohydrate and Lipid Metabolic Effects

Hyperglycemia JOLESSA 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 of duration . JOLESSA may decrease glucose tolerance. Carefully monitor prediabetic and diabetic females who are using JOLESSA. Dyslipidemia Consider alternative contraception for females with uncontrolled dyslipidemia. JOLESSA may cause adverse lipid changes.

Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using JOLESSA, which may increase the risk of pancreatitis.

5.8Headache

JOLESSA is contraindicated in females who have headaches with focal neurological symptoms or have migraine headaches with aura, and in women over age 35 years who have migraine headaches with or without aura . If a female taking JOLESSA develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue JOLESSA if indicated. Consider discontinuation of JOLESSA if there is an increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) .

5.9Bleeding Irregularities and Amenorrhea Bleeding

and/or spotting that occurs at any time while taking the first 84 tablets of each extended-cycle regimen is considered “unscheduled” bleeding/spotting. Bleeding that occurs during the time a woman takes the seven white inert tablets is considered “scheduled” bleeding. Unscheduled Bleeding and Spotting Females using JOLESSA 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, evaluate for causes such as pregnancy or malignancy. Before prescribing JOLESSA, advise the woman to weigh the occurrence of fewer scheduled menses (4 per year instead of 13 per year) against the occurrence of increased unscheduled bleeding and/or spotting.

The clinical trial of the efficacy of JOLESSA (91-day cycles) in preventing pregnancy also assessed scheduled and unscheduled bleeding. The participants in the study were composed primarily of women who had used oral contraceptives previously as opposed to new users. Women with a history of breakthrough bleeding/spotting ≥ 10 consecutive days on oral contraceptives were excluded from the study.

More JOLESSA subjects, compared to subjects on the comparator 28-day cycle regimen, discontinued prematurely for unacceptable bleeding (7.7% [JOLESSA] vs. 1.8% [28-day cycle regimen]). Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. Table 3 below presents the number of days with unscheduled bleeding and/or spotting for each respective 91-day cycle.

Table 3: Number of Unscheduled Bleeding and/or Spotting Days per 91-day Cycle Cycle (N) Days of Unscheduled Bleeding and/or Spotting per 84-Day Interval Median Days Per Subject-Month Mean Q1 Median Q3 1 15.1 3.0 12 23.0 3.0 2 11.6 2.0 6 17.5 1.5 3 10.6 1.0 6 15.0 1.5 4 8.8 1.0 4 14.0 1.0 Q1=Quartile 1: 25% of women had ≤ this number of days of unscheduled bleeding/spotting Median: 50% of women had ≤ this number of days of unscheduled bleeding/spotting Q3=Quartile 3: 75% of women had ≤ this number of days of unscheduled bleeding/spotting Table 4 shows the percentages of women with ≥7 days and ≥20 days of unscheduled spotting and/or bleeding in the JOLESSA and the 28-day cycle treatment groups. Table 4: Percentage of Subjects with Unscheduled Bleeding and/or Spotting Days of unscheduled bleeding and/or spotting Percentage of Subjects a JOLESSA Cycle 1 (N=385) Cycle 4 (N=261) ≥ 7 days 65% 42% ≥ 20 days 35% 15% 28-day regimen Cycles 1-4 (N=194) Cycles 10-13 (N=158) ≥ 7 days 38% 39% ≥ 20 days 6% 4% a Based on spotting and/or bleeding on days 1-84 of a 91 day cycle in the JOLESSA subjects and days 1-21 of a 28 day cycle over 4 cycles in the 28-day dosing regimen. Total days of bleeding and/or spotting (scheduled plus unscheduled) were similar over one year of treatment for JOLESSA subjects and subjects on the 28-day cycle regimen.

Amenorrhea and Oligomenorrhea Females who use JOLESSA may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant. Based on data from the clinical trial of JOLESSA, amenorrhea occurred in approximately 0.8% of females during Cycle 1, 1.2% of females during Cycle 2, 3.7% of females during Cycle 3, and 3.4% of females during Cycle 4. Because females using JOLESSA will likely have scheduled bleeding only 4 times per year, rule out pregnancy at the time of any missed menstrual period.

After discontinuation of JOLESSA, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent.

5.10Depression Carefully

observe females with a history of depression and discontinue JOLESSA if depression recurs to a serious degree. Data on the association of COCs with onset of depression or exacerbation of existing depression are limited.

5.11Malignant Neoplasms Breast Cancer

JOLESSA 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 COC are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia.

However, there is controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

5.12Effect on Binding Globulins The

estrogen component of JOLESSA 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.

5.13Hereditary Angioedema In

females with hereditary angioedema, exogenous estrogens, including JOLESSA, may induce or exacerbate symptoms of hereditary angioedema.

5.14Chloasma Chloasma

may occur with JOLESSA 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 JOLESSA.

4 CONTRAINDICATIONS JOLESSA 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 . Have current or history of deep vein thrombosis or pulmonary embolism . Have cerebrovascular disease . Have coronary artery disease . Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) . Have inherited or acquired hypercoagulopathies . Have uncontrolled hypertension or hypertension with vascular disease . Have diabetes mellitus and are over age of 35, diabetes mellitus with hypertension or vascular disease or other end-organ damage, or diabetes mellitus of >20 years duration . Have headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches . Current diagnosis of, or history of breast cancer, which may be hormone sensitive . Liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis . Undiagnosed abnormal uterine bleeding . Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations . A high risk of arterial or venous thrombotic diseases Liver tumors or liver disease, acute viral hepatitis or decompensated cirrhosis Undiagnosed abnormal uterine bleeding Breast cancer Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir.

8.1Pregnancy Risk Summary There

is no use for contraception in pregnancy; therefore, JOLESSA should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to COCs before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 percent and 15 to 20 percent, respectively.

The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: Serious cardiovascular events and stroke Vascular events Liver disease The most common adverse reactions (≥2%) reported during clinical trials were headache, menorrhagia, nausea, dysmenorrhea, acne, migraine, breast tenderness, weight increased, and depression. 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 .

6.1Clinical 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 clinical practice. The clinical trial that evaluated the safety and efficacy of JOLESSA was a 12-month, randomized, multicenter, open-label study, which enrolled women aged 18 to 40, of whom 456 took at least one dose of JOLESSA (345.14 woman-years of exposure) . Adverse Reactions Leading to Study Discontinuation: 14.9% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions (≥ 1% of women) leading to discontinuation in the JOLESSA group were menorrhagia (5.7%), mood swings (1.9%), weight/appetite increase (1.5%), and acne (1.3%). Common Adverse Reactions (≥ 2% of women): headache (20.6%), menorrhagia (11.6%), nausea (7.5%), dysmenorrhea (5.7%), acne (4.6%), migraine (4.4%), breast tenderness (3.5%), weight increased (3.1%), and depression (2.1%).

Serious Adverse Reactions: pulmonary embolus, cholecystitis.

6.2Postmarketing 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 JOLESSA. Because these reactions are reported voluntarily from a population of uncertain size, it is not 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 disorder: hypersensitivity reactions, including itching, rash, and angioedema 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 Skin and subcutaneous tissue disorders: alopecia Vascular disorders: thrombosis, pulmonary embolism, pulmonary thrombosis Figure breast cancer data