These highlights do not include all the information needed to use JOLESSA safely and effectively. See full prescribing information for JOLESSA.JOLESSA® (levonorgestrel and ethinyl estradiol tablets) for oral useInitial U.S. Approval: 1982

RECENT MAJOR CHANGES

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs, including JOLESSA, are contraindicated in women who are over 35 years of age and smoke [see Contraindications (4) and Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

JOLESSA® is indicated for use by females of reproductive potential to prevent pregnancy.

2 DOSAGE AND ADMINISTRATION

2.1 How to Start and Take JOLESSA

JOLESSA is dispensed in an Extended-Cycle Tablet Dispenser [see How Supplied/Storage and Handling (16)]. JOLESSA should be started on a Sunday (see Table 1). 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 after Abortion or Miscarriage

First-trimester

Second-trimester

Starting JOLESSA after Childbirth

• 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.

2.2 Dosing 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.

2.3 Missed Doses

Table 2:          Instructions for Missed JOLESSA Tablets

2.4 Advice in Case of Gastrointestinal Disturbances

In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting or diarrhea occurs within 3-4 hours after taking a pink tablet, handle this as a missed tablet.

3 DOSAGE FORMS AND STRENGTHS

JOLESSA (levonorgestrel and ethinyl estradiol tablets) are available as round, film-coated, biconvex, unscored tablets with a debossed stylized b on one side, packaged in Extended-Cycle Tablet Dispensers, each containing a 13-week supply of tablets in the following order:

• 84 pink tablets, each containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol; debossed with 992 on the other side
• 7 white inert tablets debossed with 208 on the other side.

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:

5 WARNINGS AND PRECAUTIONS

5.1 Thromboembolic Disorders and Other Vascular Conditions

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 [see Contraindications (4)]. Cigarette smoking increases the risk of serious cardiovascular events from COC use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked.

Venous Events

Use of COCs increases the risk of venous thromboembolic events (VTEs), such as deep vein thrombosis and pulmonary embolism. Risk factors for VTEs include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of COCs [see Contraindications (4)]. While the increased risk of VTE associated with use of COCs is well-established, the rates of VTE are even greater during pregnancy, and especially during the postpartum period (see Figure 1). The rate of VTE in females using COCs has been estimated to be 3 to 9 cases per 10,000 woman years.

The risk of VTE is highest during the first year of use of a COC and when restarting hormonal contraception after a break of four weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued.

Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use oral contraceptives, for females who use oral contraceptives, 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.

• 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 [see Contraindications (4)].

5.2 Liver Disease

Elevated Liver Enzymes

JOLESSA is contraindicated in females with acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see Contraindications (4)]. Acute liver test abnormalities may necessitate the discontinuation of 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 [see Contraindications (4)]. COCs increase the risk of hepatic adenomas. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death 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.

5.3 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications, such as JOLESSA. Discontinue JOLESSA prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4)]. JOLESSA can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

5.4 Hypertension

JOLESSA is contraindicated in females with uncontrolled hypertension or hypertension with vascular disease [see Contraindications (4)]. 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.

5.5 Age-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 [see Contraindications (4) and Warnings and Precautions (5.1)]. Consider the presence of underlying risk factors that may increase the risk of cardiovascular disease or VTE, particularly before initiating JOLESSA for women over 35 years, such as:

• Hypertension
• Diabetes
• Dyslipidemia
• Obesity

5.6 Gallbladder Disease

Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs, including 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.

5.7 Adverse 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 [see Contraindications (4)]. 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.

5.8 Headache

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 [see Contraindications (4)].

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) [see Contraindications (4)].

5.9 Bleeding 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

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

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.

5.10 Depression

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.

5.11 Malignant Neoplasms

Breast Cancer

JOLESSA is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4)].

Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use [see Postmarketing Experience (6.2)].

Cervical Cancer

Some studies suggest that 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.

5.12 Effect 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.

5.13 Hereditary Angioedema

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

5.14 Chloasma

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.

6 ADVERSE REACTIONS

The following serious adverse reactions with the use of COCs 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 (5.2)]

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in 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) [see Clinical Studies (14)].

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.

6.2 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 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

7 DRUG INTERACTIONS

The sections below provide information on substances for which data on drug interactions with COCs are available. There is little information available about the clinical effect of most drug interactions that may affect COCs. However, based on the known pharmacokinetic effects of these drugs, clinical strategies to minimize any potential adverse effect on contraceptive effectiveness or safety are suggested.

Consult the approved product labeling of all concurrently used drugs to obtain further information about interactions with COCs or the potential for metabolic enzyme or transporter system alterations.

No drug-drug interaction studies were conducted with JOLESSA.

7.1 Effects of Other Drugs on Combined Oral Contraceptives

Substances decreasing the plasma concentrations of COCs and potentially diminishing the efficacy of COCs:

Table 5 includes substances that demonstrated an important drug interaction with JOLESSA.

Table 5:          Significant Drug Interactions Involving Substances That Affect COCs

a Induction potency of St. John’s wort may vary widely based on preparation.

Substances increasing the systemic exposure of COCs:

Co-administration of atorvastatin or rosuvastatin and certain COCs containing ethinyl estradiol (EE) increase AUC values for EE by approximately 20-25%. Ascorbic acid and acetaminophen may increase systemic exposure of EE possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase systemic exposure of estrogen and/or progestin component of COCs.

Human immunodeficiency virus (HIV)/ Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors:

Significant decreases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with some HIV protease inhibitors (e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or some HCV protease inhibitors (e.g. boceprevir and telaprevir) and some non-nucleosidase reverse transcriptase inhibitors (e.g. nevirapine).

In contrast, significant increases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with certain other HIV protease inhibitors (e.g. indinavir and atazanavir/ritonavir) and with other non-nucleoside reverse transcriptase inhibitors (e.g. etravirine).

7.2 Effects of Combined Oral Contraceptives on Other Drugs

Table 6 provides significant drug interaction information for drugs co-administered with JOLESSA.

Table 6:          Significant Drug Interaction Information for Drugs Co-Administered With COCs

7.3 Concomitant Use with Hepatitis C Virus (HCV) Combination Therapy – Liver Enzyme Elevation

Co-administration of JOLESSA with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir is contraindicated due to potential for ALT elevations [see Warnings and Precautions (5.3)]. Co-administration of JOLESSA and glecaprevir/pibrentasvir is not recommended due to potential for ALT elevations.

7.4 Effect on Laboratory Tests

The use of COCs may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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.

8.2 Lactation

Risk Summary

Contraceptive hormones and/or metabolites are present in human milk. COCs can reduce milk production in breastfeeding females. This reduction can occur at any time but is less likely to occur once breastfeeding is well-established. When possible, advise the nursing female to use other methods of contraception until she discontinues breastfeeding [see Dosage and Administration (2.1)].  The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for JOLESSA and any potential adverse effects on the breastfed child from JOLESSA or the underlying maternal condition.

8.4 Pediatric Use

Safety and efficacy of JOLESSA have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 as for users 18 years and older. Use of JOLESSA before menarche is not indicated.

8.5 Geriatric Use

JOLESSA has not been studied in postmenopausal women and is not indicated in this population.

8.6 Hepatic Impairment

The pharmacokinetics of JOLESSA have not been studied in subjects with hepatic impairment. However, COCs may be poorly metabolized in patients with hepatic impairment. JOLESSA is contraindicated in females with acute hepatitis or severe decompensated cirrhosis [see Contraindications (4) and Warnings and Precautions (5.2)].

10 OVERDOSAGE

There have been no reports of serious ill effects from overdose of oral contraceptives, including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea.

11 DESCRIPTION

JOLESSA (levonorgestrel and ethinyl estradiol tablets) is an extended-cycle combination oral contraceptive consisting of 84 pink active tablets each containing 0.15 mg of levonorgestrel, a synthetic progestin and 0.03 mg of ethinyl estradiol, an estrogen, and 7 white inert tablets (without hormones).

The structural formulas for the active components are:

Levonorgestrel

C21H28O2 MW: 312.4

Levonorgestrel is chemically 18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-, (17α)-, (-)-.

Ethinyl Estradiol

C20H24O2 MW: 296.4

Ethinyl Estradiol is 19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-.

• Each pink active tablet contains the following inactive ingredients: anhydrous lactose NF, FD&C blue no. 1, FD&C red no. 40, hydroxypropyl methylcellulose USP, microcrystalline cellulose NF, polyethylene glycol NF, magnesium stearate NF, polysorbate 80 NF, and titanium dioxide USP.
• Each white inert tablet contains the following inactive ingredients: anhydrous lactose NF, hydroxypropyl methylcellulose USP, microcrystalline cellulose NF, and magnesium stearate NF.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

COCs prevent pregnancy primarily by suppressing ovulation. 

12.2 Pharmacodynamics

No specific pharmacodynamic studies were conducted with JOLESSA.

12.3 Pharmacokinetics

Absorption

No specific investigation of the absolute bioavailability of JOLESSA in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability nearly 100%) and is not subject to first-pass metabolism. EE is rapidly and almost completely absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, the bioavailability of EE is approximately 43%.

Following continuous dosing with once-daily administration of JOLESSA tablets, plasma concentrations of levonorgestrel and EE reached steady-state within 7 days. The mean plasma pharmacokinetic parameters for JOLESSA under fasting conditions in normal healthy women following once-daily administration of one levonorgestrel/EE combination tablet for 10 days are summarized in Table 7.

Table 7: Mean ±SD Pharmacokinetic Parameters Under Fasting Conditions in Healthy Women Following 10 Days Administration of One Tablet of JOLESSA (n=44)

a Cavg = AUC0-24/24

Food Effect

The effect of food on the rate and the extent of levonorgestrel and EE absorption following oral administration of JOLESSA has not been evaluated.

Distribution

The apparent volume of distribution of levonorgestrel and EE are reported to be approximately 1.8 L/kg and 4.3 L/kg, respectively. Levonorgestrel is about 97.5 - 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin. EE is about 95 - 97% bound to serum albumin. EE does not bind to SHBG, but induces SHBG synthesis, which leads to decreased levonorgestrel clearance. Following repeated daily dosing of levonorgestrel/EE oral contraceptives, levonorgestrel plasma concentrations accumulate more than predicted based on single-dose pharmacokinetics, due in part, to increased SHBG levels that are induced by EE, and a possible reduction in hepatic metabolic capacity.

Metabolism

Following absorption, levonorgestrel is conjugated at the 17β-OH position to form sulfate and to a lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3α,5β-tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3α,5α-tetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. Levonorgestrel and its phase I metabolites are excreted primarily as glucuronide conjugates. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users.

First-pass metabolism of EE involves formation of EE-3-sulfate in the gut wall, followed by 2-hydroxylation of a portion of the remaining untransformed EE by hepatic cytochrome P-450 3A4 (CYP3A4). Levels of CYP3A4 vary widely among individuals and can explain the variation in rates of EE hydroxylation. Hydroxylation at the 4-, 6-, and 16- positions may also occur, although to a much lesser extent than 2-hydroxylation. The various hydroxylated metabolites are subject to further methylation and/or conjugation.

Excretion

About 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. The terminal elimination half-life for levonorgestrel after a single dose of JOLESSA was about 30 hours.

EE is excreted in the urine and feces as glucuronide and sulfate conjugates, and it undergoes enterohepatic recirculation. The terminal elimination half-life of EE after a single dose of JOLESSA was found to be about 15 hours.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

See Warnings and Precautions (5.2, 5.11).

14 CLINICAL STUDIES

In a 12-month, multicenter, randomized, open-label clinical trial, 456 women aged 18-40 were studied to assess the safety and efficacy of JOLESSA, completing 809 91-day cycles of exposure. The racial demographic of those enrolled was: Caucasian (77%), African-American (11%), Hispanic (7%), Asian (2%), and Other (3%). There were no exclusions for body mass index (BMI) or weight. The weight range of those women treated was 84 to 304 pounds, with a mean weight of 157 pounds and a median weight of 147 pounds. Among the women in the trial, 63% were current or recent hormonal contraceptive users, 29% were prior users (who had used hormonal contraceptives in the past but not in the 6 months prior to enrollment), and 8% were new starts.

The pregnancy rate (Pearl Index [PI]) in the 397 women aged 18-35 years was 1.98 pregnancies per 100 women-years of use (95% CI: 0.54 to 5.03), based on 4 pregnancies that occurred after the onset of treatment and within 14 days after the last combination pill. Cycles in which conception did not occur, but which included the use of back-up contraception, were not included in the calculation of the PI.

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

JOLESSA (levonorgestrel and ethinyl estradiol tablets) are available as round, film-coated, biconvex, unscored tablets with a debossed stylized b on one side, packaged in Extended-Cycle Tablet Dispensers, each containing a 13-week supply of tablets in the following order:

Box of 3 Extended-Cycle Tablet Dispensers      NDC 0555-9123-66

Storage and Handling

• 84 pink tablets, each containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol: debossed with 992 on the other side
• 7 white inert tablets debossed with 208 on the other side

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Cigarette Smoking

Cigarette smoking increases the risk of serious cardiovascular events from COC use. Women who are over 35 years old and smoke should not use JOLESSA [see Boxed Warning and Warnings and Precautions (5.1)].

Venous Thromboembolism

The increased risk of VTE compared to non-users of COCs is greatest after initially starting a COC or restarting (following a 4-week or greater pill-free interval) the same or a different COC [see Warnings and Precautions (5.1)].

Use During Pregnancy

Instruct females to stop further intake of JOLESSA if pregnancy is confirmed during treatment.

Sexually Transmitted Infections

JOLESSA does not protect against HIV-infection (AIDS) and other sexually transmitted infections.

Dosing and Missed Pill Instructions

Need for Additional Contraception

Lactation

JOLESSA may reduce breast milk production. This is less likely to occur if breastfeeding is well established. When possible, nursing women should use other methods of contraception until they have discontinued breastfeeding [see Use in Specific Populations (8.2)].

Amenorrhea and Possible Symptoms of Pregnancy

Amenorrhea may occur. Because women using JOLESSA will likely have scheduled bleeding only 4 times per year, advise women to contact their health care provider in the event of amenorrhea with symptoms of pregnancy such as morning sickness or unusual breast tenderness [see Warnings and Precautions (5.9)].

Depression

Depressed mood and depression may occur. Women should contact their healthcare provider if mood changes and depressive symptoms occur, including shortly after initiating the treatment [see Warnings and Precautions (5.10)].

Manufactured for: Teva Pharmaceuticals Parsippany, NJ 07054

JOL-004

Revised: 01/2023

© 2023 Teva Pharmaceuticals, Inc.

• Patients should take one tablet daily by mouth at the same time every day [see Dosage and Administration (2.1)].
• Instruct patients what to do in the event tablets are missed. See “What should I do if I miss any JOLESSA pills” section in FDA-approved Instructions for Use [see Dosage and Administration (2.3)].

FDA-approved Patient Labeling

PATIENT INFORMATION

JOLESSA® [joe les’ a]

(levonorgestrel and ethinyl estradiol tablets)

WARNING TO WOMEN WHO SMOKE

Do not use JOLESSA if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects from birth control pills, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke.

What is the most important information I should know about JOLESSA?

Do not use JOLESSA if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects from birth control pills, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke.

What is JOLESSA?

JOLESSA is a birth control pill (oral contraceptive) used by women to prevent pregnancy. It contains two female hormones, an estrogen called ethinyl estradiol, and a progestin called levonorgestrel. JOLESSA does not protect against HIV infections (AIDS) and other sexually transmitted infections.

How does JOLESSA work for contraception?

Your chance of getting pregnant depends on how well you follow the directions for taking your birth control pills. The better you follow the directions, the less chance you have of getting pregnant.

Based on the results of clinical studies, about 1 to 5 out of 100 women may get pregnant during the first year they use JOLESSA.

The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant.

Who should not take JOLESSA?

Do not take JOLESSA if you:

If any of these conditions happen to you while you are taking JOLESSA, stop taking JOLESSA right away and talk to your healthcare provider. Use non-hormonal contraception when you stop taking JOLESSA.

What should I tell my healthcare provider before taking JOLESSA?

Tell your healthcare provider if you:

Tell your healthcare provider if you have ever had any of the conditions listed in, “Who should not take JOLESSA” above. Your healthcare provider may recommend another method of birth control.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.

JOLESSA may affect the way other medicines work, and other medicines may affect how well JOLESSA works.

Some medicines and herbal products may make birth control pills less effective, including:

Use a back-up or alternative birth control method when you take medicines that may make birth control pills less effective.

Birth control pills may interact with lamotrigine, an anticonvulsant used for epilepsy. This may increase the risk of seizures, so your physician may need to adjust the dose of lamotrigine.

Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I take JOLESSA?

Read the Instructions for Use at the end of this Patient Information.

What are the most serious risks of taking JOLESSA?

Like pregnancy, JOLESSA may cause serious side effects, including blood clots in your lungs, heart attack, or a stroke that may lead to death. Some other examples of serious blood clots include blood clots in the legs or eyes. Serious blood clots can happen especially if you smoke, are obese, or are older than 35 years of age. Serious blood clots are more likely to happen when you:

Call your healthcare provider or go to a hospital emergency room right away if you have:

Other serious side effects include:

What are the most common side effects of JOLESSA?

These are not all the possible side effects of JOLESSA. For more information, ask your healthcare provider or pharmacist. You may report side effects to the FDA at 1-800-FDA-1088.

What else should I know about taking JOLESSA?

How should I store JOLESSA?

General information about the safe and effective use of JOLESSA.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use JOLESSA for a condition for which it was not prescribed. Do not give JOLESSA to other people, even if they have the same symptoms that you have.

This Patient Information summarizes the most important information about JOLESSA. You can ask your pharmacist or healthcare provider for information about JOLESSA that is written for health professionals.

For more information, call 1-888-483-8279 (1-888-4Teva-RX).

Do birth control pills cause cancer?

It is not known if hormonal birth control pills cause breast cancer. Some studies, but not all, suggest that there could be a slight increase in the risk of breast cancer among current users with longer duration of use.

If you have breast cancer now, or have had it in the past, do not use hormonal birth control because some breast cancers are sensitive to hormones. Women who use birth control pills may have a slightly higher chance of getting cervical cancer. However, this may be due to other reasons such as having more sexual partners.

What if I want to become pregnant?

You may stop taking the pill whenever you wish. Consider a visit with your healthcare provider for a pre-pregnancy checkup before you stop taking the pill.

What should I know about my period when taking JOLESSA?

When you take JOLESSA, which has a 91-day extended dosing cycle, you should have 4 scheduled periods a year (bleeding when you are taking the 7 white pills). However, you will probably have more bleeding or spotting between your scheduled periods than if you were using a birth control pill with a 28-day dosing cycle. During the first JOLESSA 91-day treatment cycle, about 1 in 3 women may have 20 or more days of unplanned bleeding or spotting. This bleeding or spotting tends to decrease with time. Do not stop taking JOLESSA because of this bleeding or spotting. If the spotting continues for more than 7 days in a row or if the bleeding is heavy, call your healthcare provider.

What if I miss my scheduled period when taking JOLESSA?

You should consider the possibility that you are pregnant if you miss your scheduled period (no bleeding on the days that you are taking white pills). Since scheduled periods are less frequent when you are taking JOLESSA, notify your healthcare provider that you have missed your period and that you are taking JOLESSA. Also notify your healthcare provider if you have symptoms of pregnancy such as morning sickness or unusual breast tenderness. It is important that your healthcare provider evaluates you to determine if you are pregnant. Stop taking JOLESSA if it is determined that you are pregnant.

What are the ingredients in JOLESSA?

Active ingredients: Each pink pill contains levonorgestrel and ethinyl estradiol.

Inactive ingredients:

Pink pills: anhydrous lactose NF, FD&C blue no. 1, FD&C red no. 40, hydroxypropyl methylcellulose USP, microcrystalline cellulose NF, polyethylene glycol NF, magnesium stearate NF, polysorbate 80 NF, and titanium dioxide USP.

White pills: anhydrous lactose NF, hydroxypropyl methylcellulose USP, microcrystalline cellulose NF, and magnesium stearate NF.

• smoke and are over 35 years of age
• have or had blood clots in your arms, legs, lungs, or eyes
• had a stroke
• had a heart attack
• have certain heart valve problems or heart rhythm abnormalities that can cause blood clots to form in the heart
• have or had a problem with your blood that makes it clot more than normal
• have high blood pressure that cannot be controlled by medicine or have high blood pressure with blood vessels problems
• have diabetesand are over the age of 35with high blood pressurewith kidney, eye, nerve, or blood vessel damage for more than 20 years
• have certain kinds of severe migraine headaches with aura, numbness, weakness or changes in vision, or any migraine headaches if you are over 35 years of age
• have or had breast cancer
• have liver problems, including liver tumors
• have any unexplained vaginal bleeding
• take any Hepatitis C drug combination containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. This may increase levels of the liver enzyme “alanine aminotransferase” (ALT) in the blood.

INSTRUCTIONS FOR USE

JOLESSA® [joe les’ a]

(levonorgestrel and ethinyl estradiol tablets)

Important information about taking JOLESSA

Before you start taking JOLESSA:

Figure A

Figure B

When should I start taking JOLESSA?

If you start taking JOLESSA and you have not used a hormonal birth control method before:

If you have recently given birth and have not yet had a period, use another method of birth control if you have sex (such as condoms and spermicides) as a back-up method until you have taken JOLESSA for 7 days.

If you start taking JOLESSA and you are switching from another birth control pill:

If you start taking JOLESSA and previously used a vaginal ring:

If you start taking JOLESSA and previously used a transdermal patch:

If you start taking JOLESSA and you are switching from a progestin-only method such as an implant or injection:

If you start taking JOLESSA and you are switching from an intrauterine device or system (IUD or IUS):

Keep a calendar to track your period: If this is the first time you are taking birth control pills, read, “When should I start taking JOLESSA?” above. Follow these instructions for a Sunday Start.

Instructions for using your JOLESSA Extended-Cycle Tablet Dispenser:

Sunday Start:

Figure C

What should I do if I miss any JOLESSA pills?

If you miss 1 pink pill, follow these steps:

If you miss 2 pink pills in a row, follow these steps:

If you miss 3 or more pink pills in a row, follow these steps:

If you miss any of the 7 white pills:

Finally, if you are still not sure what to do about the pills you have missed

If you have any questions or are unsure about the information in this leaflet, call your healthcare provider.

Manufactured for: Teva Pharmaceuticals Parsippany, NJ 07054

This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.

JOLPL-004

Revised: 01/2023

©2023 Teva Pharmaceuticals, Inc.

• Take 1 pill every day at the same time. Take the pills in the order directed on your pill dispenser.
• Do not skip your pills, even if you do not have sex often. If you miss pills (including starting the pack late) you could get pregnant. The more pills you miss, the more likely you are to get pregnant.
• If you have trouble remembering to take JOLESSA, talk to your healthcare provider.
• When you first start taking JOLESSA, spotting or light bleeding in between your periods may occur. Contact your healthcare provider if this does not go away after a few months.
• You may feel sick to your stomach (nauseous), especially during the first few months of taking JOLESSA. If you feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If your nausea does not go away, call your healthcare provider.
• Missing pills can also cause spotting or light bleeding, even when you take the missed pills later. On the days you take 2 pills to make up for missed pills (see, “What should I do if I miss any JOLESSA pills?” below), you could also feel a little sick to your stomach.
• It is not uncommon to miss a period. However, if you miss a period and have not taken JOLESSA according to directions, or feel like you may be pregnant, call your healthcare provider. If you have a positive pregnancy test, you should stop taking JOLESSA.
• If you have vomiting or diarrhea within 3-4 hours of taking a pink pill, take another pink pill as soon as possible. Continue taking one pill a day until the 91-day course is finished.
• If you have vomiting or diarrhea for more than 1 day, your birth control pills may not work as well. Use an additional birth control method, like condoms or spermicide, until you check with your healthcare provider.
• Stop taking JOLESSA at least 4 weeks before you have major surgery and do not restart after the surgery without asking your healthcare provider. Be sure to use other forms of contraception (like condoms or spermicide) during this time period.

Jolessa 0.15mg/0.03mg Tablets 91-Day Regimen