Jolessa (Page 6 of 9)

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)

Analyte	AUC0-24	Cmax	Cmin	Cavg a	Tmax
Levonorgestrel	54.6 ± 16.5 ng*hr/mL	5.0 ± 1.5 ng/mL	1.6 ± 0.5 ng/mL	2.3 ± 0.7 ng/mL	1.4 ± 0.7 hours
Ethinyl estradiol	935.5 ± 346.9 pg*hr/mL	106.1 ± 41.2 pg/mL	18.5 ± 9.4 pg/mL	38.9 ± 14.4 pg/mL	1.6 ± 0.6 hours

^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:

• 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.

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

• 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 back-up 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-004

Revised: 01/2023

© 2023 Teva Pharmaceuticals, Inc.