Professional Information — Jolessa

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. (1)

Dosage and Administration

• Take one tablet daily by mouth at the same time every day for 91 days. (2.1)
• Take tablets in the order directed on the Extended-Cycle Tablet Dispenser. (2.2)

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

• 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 [see Contraindications (4), Warnings and Precautions (5.1)].

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 [see Use in Specific Populations (8.2)].
• If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of JOLESSA [see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.1 and 8.2)].

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.

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.

JOLESSA consists of 84 round, pink tablets containing 0.15 mg of levonorgestrel and 0.03 mg of ethinyl estradiol, and 7 round, white inert tablets. (3)

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 [see Boxed Warning and Warnings and Precautions (5.1)].
• Have current or history of deep vein thrombosis or pulmonary embolism [see Warnings and Precautions ( 5.1 )].
• Have cerebrovascular disease [see Warnings and Precautions ( 5.1 )].
• Have coronary artery disease [see Warnings and Precautions ( 5.1 )].
• Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions ( 5.1 )].
• Have inherited or acquired hypercoagulopathies [see Warnings and Precautions ( 5.1 )].
• Have uncontrolled hypertension or hypertension with vascular disease [see Warnings and Precautions (5.4)].
• 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 [see Warnings and Precautions (5.7)].
• Have headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches [see Warnings and Precautions (5.8)].

• Current diagnosis of, or history of breast cancer, which may be hormone sensitive [see Warnings and Precautions (5.11)].
• Liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].
• Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.9)].
• Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [see Warnings and Precautions (5.3)].

• A high risk of arterial or venous thrombotic diseases (4)
• Liver tumors or liver disease, acute viral hepatitis or decompensated cirrhosis (4)
• Undiagnosed abnormal uterine bleeding (4)
• Breast cancer (4)
• Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. (4)

Warnings and Precautions

• Vascular risks: Stop if a thrombotic or thromboembolic event occurs. Stop at least 4 weeks before and through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breastfeeding. Consider cardiovascular risk factors before initiating in all females, particularly those over 35 years. (5.1, 5.5)
• Liver disease: Discontinue if jaundice occurs. (5.2)
• Hypertension: If used in women with well-controlled hypertension, monitor blood pressure and stop if blood pressure rises significantly. (5.4)
• Gallbladder disease: May cause or worsen gallbladder disease. (5.6)
• Adverse carbohydrate and lipid effects: Monitor glucose in prediabetic and diabetic women taking JOLESSA. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. (5.7)
• Headache: Evaluate significant change in headaches and discontinue if indicated. (5.8)
• Uterine bleeding: May cause irregular bleeding or amenorrhea. Evaluate for other causes if symptoms persist. (5.9)

5.1 Thromboembolic Disorders and Other Vascular Conditions

• Stop 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)].

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.

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.

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)]

The most common adverse reactions (≥2%) reported during clinical trials were headache, menorrhagia, nausea, dysmenorrhea, acne, migraine, breast tenderness, weight increased, and depression. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in 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

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.

Enzyme inducers (e.g. CYP3A4): May decrease the effectiveness of JOLESSA or increase breakthrough bleeding. Counsel patients to use a backup or alternative method of contraception when enzyme inducers are used with JOLESSA. (7.1)

7.1 Effects of Other Drugs on Combined Oral Contraceptives

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

Table 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 Warning s 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.

Use in Specific Populations

• Pregnancy: Discontinue if pregnancy occurs. (8.1)
• Lactation: Advise use of another contraceptive method; JOLESSA can decrease milk production. (8.2)

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)].

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.

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.

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.

Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

See Warnings and Precautions (5.2, 5.11).

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 backup contraception, were not included in the calculation of the PI.

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:

• 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

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

Storage and Handling

• Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF) [See USP Controlled Room Temperature].
• Protect from light.

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

• 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)].

Need for Additional Contraception

• Postpartum females who start JOLESSA who have not yet had a period when they start JOLESSA need to use an additional method of contraception until they have taken a pink tablet for 7 consecutive days [see Dosage and Administration (2.1)].
• There is a need for a backup or alternative method of contraception when enzyme inducers are used with JOLESSA [see Drug Interactions (7.1)].

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-005

Revised: 10/2024

© 2024 Teva Pharmaceuticals, Inc.