Quartette

Quartette is part of the drug class:

• Combination Progesterone and Estrogen Contraceptives

• It is used to prevent pregnancy.
• It may be given to you for other reasons. Talk with the doctor.

• If you have an allergy to ethinyl estradiol, levonorgestrel, or any other part of Quartette.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have had any of these health problems: Blood clots, blood clotting problem, breast cancer, diseased arteries in the brain, disease of a heart valve with problems, heart disease, chest pain caused by angina, heart attack, stroke, high blood pressure, high cholesterol, a pancreas problem (pancreatitis) due to high blood triglycerides, liver disease, liver tumor, very bad headache or migraine, diabetes that affects blood flow, or tumor where estrogen makes it grow.
• If you have had any of these health problems: Endometrial cancer, cancer of the cervix or vagina, or vaginal bleeding where the cause is not known.
• If you have surgery and need bedrest.
• If you turned yellow during pregnancy or with estrogen-based or hormone contraceptive use.
• If you are pregnant or may be pregnant. Do not take this medicine if you are pregnant.
• If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with Quartette.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• Tell all of your health care providers that you take Quartette. This includes your doctors, nurses, pharmacists, and dentists.
• This medicine may raise the chance of blood clots, a stroke, or a heart attack. Talk with the doctor.
• Talk with your doctor if you will need to be still for long periods of time like long trips, bedrest after surgery, or illness. Not moving for long periods may raise your chance of blood clots.
• If you have high blood sugar (diabetes), talk with your doctor. This medicine may raise blood sugar.
• Check your blood sugar as you have been told by your doctor.
• High blood pressure has happened with drugs like this one. Have your blood pressure checked as you have been told by your doctor.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Be sure to have regular breast exams and gynecology check-ups. Your doctor will tell you how often to have these. You will also need to do breast self-exams as your doctor has told you. Talk with your doctor.
• This medicine may affect certain lab tests. Tell all of your health care providers and lab workers that you take this medicine.
• Certain drugs, herbal products, or health problems could cause Quartette to not work as well. Be sure your doctor knows about all of your drugs and health problems.
• This medicine does not stop the spread of diseases like HIV or hepatitis that are passed through blood or having sex. Do not have any kind of sex without using a latex or polyurethane condom. Do not share needles or other things like toothbrushes or razors. Talk with your doctor.
• Do not use in children who have not had their first menstrual period.
• If you have any signs of pregnancy or if you have a positive pregnancy test, call your doctor right away.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

How to Take Quartette

Instruct patients to take Quartette once a day by mouth at the same time every day for 91 days. To achieve maximum contraceptive effectiveness, Quartette must be taken exactly as directed and at intervals not exceeding 24 hours. For patient instructions regarding missed pills, see FDA-approved patient labeling.

How to Start Quartette

For each 91-day course, take in the following order:

1. Start the first light pink tablet (0.15 mg of levonorgestrel and 0.02 mg ethinyl estradiol) on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, take the tablet on that day. Then take one light pink tablet once a day for a total of 42 consecutive days. Use a non-hormonal back-up method of contraception (such as condoms and spermicide) for the first 7 days of treatment. 2. One pink tablet (0.15 mg of levonorgestrel and 0.025 mg ethinyl estradiol) once a day for 21 consecutive days. 3. One purple tablet (0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol) once a day for 21 days. 4. One yellow tablet (0.01 mg of ethinyl estradiol) once a day for 7 days. Bleeding should occur during yellow tablet use.

Begin the next and all subsequent 91-day courses of Quartette without interruption on the same day of the week (i.e., Sunday) on which the patient began her first dose. Follow the same schedule as the initial 91-day course: light pink tablet once a day for 42 days, pink tablet once a day for 21 days, purple tablet once a day for 21 days, and yellow tablet once a day for 7 days. If the patient does not immediately start her next pill pack, instruct her to protect herself from pregnancy by using a non-hormonal back-up method of contraception until she has taken a light pink tablet daily for 7 consecutive days.

If unscheduled spotting or bleeding occurs, instruct the patient to continue on the same regimen. If the bleeding is persistent or prolonged, advise the patient to consult her healthcare provider.

For a postpartum woman who is not breastfeeding or after a second trimester abortion, start Quartette no earlier than four weeks postpartum due to increased risk of thromboembolism. If the patient starts on Quartette postpartum and has not yet had a period, evaluate for possible pregnancy, and instruct her to use an additional method of contraception until she has taken a light pink tablet for 7 consecutive days. Consider the possibility of ovulation and conception prior to initiation.

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 light pink, pink or purple tablet, handle this as a missed tablet [see FDA-approved patient labeling].

Mechanism of Action

COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.

Pharmacodynamics

No pharmacodynamic studies were conducted with Quartette.

Pharmacokinetics

 Absorption

Ethinyl estradiol and levonorgestrel are absorbed with maximum plasma concentrations occurring within 2 hours after Quartette administration. Levonorgestrel is completely absorbed after oral administration (bioavailability nearly 100%) and is not subject to first-pass metabolism. Ethinyl estradiol is absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, the bioavailability of ethinyl estradiol is approximately 40%. The effect of food on the rate and the extent of levonorgestrel and ethinyl estradiol absorption following oral administration of Quartette has not been evaluated.

The mean plasma pharmacokinetic parameters of levonorgestrel following administration of another levonorgestrel/ethinyl estradiol combination tablet with an equal dose of levonorgestrel for 84 days, in healthy women are reported in Table 2.

Table 2: Mean Pharmacokinetic Parameters for 150 mcg Levonorgestrel Following Administration of a Levonorgestrel/ethinyl estradiol Combination Tablet Once Daily for 84 Days

	AUC0-24 hr (mean ± SD)	Cmax (mean ± SD)	Tmax (mean ± SD)
Day 1	18.2 ± 6.1 ng•hr/mL	3.0 ± 1.0 ng/mL	1.3 ± 0.4 hours
Day 21	64.4 ± 25.1 ng•hr/mL	6.2 ± 1.6 ng/mL	1.3 ± 0.4 hours
Day 84	60.2 ± 24.6 ng•hr/mL	5.5 ± 1.6 ng/mL	1.3± 0.3 hours

Following repeated daily dosing of levonorgestrel/ethinyl estradiol 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 ethinyl estradiol, and a possible reduction in hepatic metabolic capacity.

Systemic exposure to ethinyl estradiol following administration of a LNG/EE combination tablet increases linearly in an approximate dose-proportional manner over the range of doses of 20 mcg to 30 mcg within this product. Systemic exposure to EE (as assessed by AUC) at steady state following administration of levonorgestrel/ethinyl estradiol oral contraceptives is approximately 20% higher than expected based on single-dose data for the dose range of 20-30 mcg.

Distribution

The apparent volume of distribution of levonorgestrel is reported to be approximately 1.8 L/kg. Levonorgestrel is about 97.5 - 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin.

The apparent volume of distribution of ethinyl estradiol is reported to be approximately 4.3 L/kg. Ethinyl estradiol is about 95-97% bound to serum albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis, which leads to decreased levonorgestrel clearance.

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 ethinyl estradiol involves formation of ethinyl estradiol-3-sulfate in the gut wall, followed by 2-hydroxylation of a portion of the remaining untransformed ethinyl estradiol by hepatic cytochrome P-450 3A4 (CYP3A4). Levels of CYP3A4 vary widely among individuals and can explain the variation in rates of ethinyl estradiol 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 mean terminal elimination half-life for levonorgestrel after a single dose of Quartette ranged from 36-41 hours.

Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates, and it undergoes enterohepatic recirculation. The terminal elimination half-life of ethinyl estradiol following single doses of Quartette is approximately 16.5 hours.

How Supplied

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

  • 42 light pink tablets, each containing 0.15 mg of levonorgestrel and 0.02 mg ethinyl estradiol: debossed with 076 on the other side • 21 pink tablets containing 0.15 mg of levonorgestrel and 0.025 mg ethinyl estradiol: debossed with 075 on the other side • 21 purple tablets containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol: debossed with 074 on the other side and • 7 yellow tablets containing 0.01 mg of ethinyl estradiol: debossed with 077 on the other side

Box of 2 Extended-Cycle Tablet Dispensers NDC 51285-431-87

Storage Conditions

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

See FDA-approved patient labeling(Patient Information).

Counsel patients on the following information:

  • Cigarette smoking increases the risk of serious cardiovascular events from COC use, and that women who are over 35 years old and smoke should not use COCs. • 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. • Quartette does not protect against HIV-infection (AIDS) and other sexually transmitted infections. • The Warnings and Precautions associated with COCs. • Quartette is not to be used during pregnancy; if pregnancy occurs during use of Quartette, instruct the patient to stop further intake. • Take one tablet daily by mouth at the same time every day. Instruct patients what to do in the event pills are missed. See WHAT TO DO IF YOU MISS PILLS section of FDA-Approved Patient Labeling. • Use a back-up or alternative method of contraception when enzyme inducers are used with COCs. • COCs may reduce breast milk production. This is less likely to occur if breastfeeding is well established. • Women who start COCs postpartum, and who have not yet had a period, should use an additional method of contraception until they have taken a light pink tablet for 7 consecutive days. • Amenorrhea may occur. Consider pregnancy in the event of amenorrhea, and rule out pregnancy if amenorrhea is associated with symptoms of pregnancy, such as morning sickness or unusual breast tenderness.

Manufactured by:

TEVA WOMEN'S HEALTH, INC.

Subsidiary of TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. 8/2017

U.S. Patent 8,415,332; 8,450,299

Quartette® Tablets (levonorgestrel/ethinyl estradiol [0.15 mg/0.02 mg, 0.15 mg/0.025 mg, 0.15 mg/0.03 mg] and ethinyl estradiol [0.01 mg]), 2 Extended-Cycle Tablet Dispensers, 91 Tablets Each, Carton Text

2 Extended-Cycle Tablet Dispensers, 91 Tablets Each

NDC 51285-431-87

Quartette®

(levonorgestrel/ethinyl estradiol) tablets

0.15 mg/0.02 mg, 0.15 mg/0.025 mg, 0.15 mg/0.03 mg

(ethinyl estradiol) tablets

  1.%2 mg

Rx only

Usual Dosage:

One tablet daily for 91 consecutive days in the following order: 42 light pink tablets each

containing 0.15 mg levonorgestrel and 0.02 mg ethinyl estradiol, 21 pink tablets each containing

0.15 mg of levonorgestrel and 0.025 mg ethinyl estradiol, and 21 purple tablets each containing

0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol, and 7 yellow tablets each containing

0.01 mg of ethinyl estradiol.

Pharmacist: Dispense patient information with each prescription.

TEVA Women’s Health

Manufactured by:

TEVA WOMEN’S HEALTH, INC.

Subsidiary of TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Quartette  levonorgestrel/ethinyl estradiol and ethinyl estradiol kit

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:51285-431

Packaging # Item Code Package Description 1 NDC:51285-431-65 1 POUCH in 1 CARTON 1 1 KIT in 1 POUCH 2 NDC:51285-431-82 1 POUCH in 1 CARTON 2 1 KIT in 1 POUCH 3 NDC:51285-431-87 2 POUCH in 1 CARTON 3 1 KIT in 1 POUCH

Quantity of Parts Part # Package Quantity Total Product Quantity Part 1 42  Part 2 21  Part 3 21  Part 4 7

Part 1 of 4 LEVONORGESTREL/ETHINYL ESTRADIOL  levonorgestrel/ethinyl estradiol tablet, film coated

Product Information Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LEVONORGESTREL (LEVONORGESTREL) LEVONORGESTREL 0.15 mg ETHINYL ESTRADIOL (ETHINYL ESTRADIOL) ETHINYL ESTRADIOL 0.02 mg

Inactive Ingredients Ingredient Name Strength ANHYDROUS LACTOSE   D&C RED NO. 27   FD&C BLUE NO. 2   INDIGOTINDISULFONATE SODIUM   FD&C YELLOW NO. 6   HYPROMELLOSE 2208 (3 MPA.S)   HYPROMELLOSE, UNSPECIFIED   LACTOSE MONOHYDRATE   MICROCRYSTALLINE CELLULOSE   MAGNESIUM STEARATE   POLYETHYLENE GLYCOL, UNSPECIFIED   TITANIUM DIOXIDE   TRIACETIN

Product Characteristics Color PINK (light pink) Score no score Shape ROUND Size 6mm Flavor Imprint Code TV;076 Contains

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA204061 07/25/2013

Part 2 of 4 LEVONORGESTREL/ETHINYL ESTRADIOL  levonorgestrel/ethinyl estradiol tablet, film coated

Product Information Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LEVONORGESTREL (LEVONORGESTREL) LEVONORGESTREL 0.15 mg ETHINYL ESTRADIOL (ETHINYL ESTRADIOL) ETHINYL ESTRADIOL 0.025 mg

Inactive Ingredients Ingredient Name Strength ANHYDROUS LACTOSE   D&C RED NO. 27   FD&C BLUE NO. 2   INDIGOTINDISULFONATE SODIUM   HYPROMELLOSE 2208 (3 MPA.S)   HYPROMELLOSE, UNSPECIFIED   LACTOSE MONOHYDRATE   MICROCRYSTALLINE CELLULOSE   MAGNESIUM STEARATE   POLYETHYLENE GLYCOL, UNSPECIFIED   TITANIUM DIOXIDE   TRIACETIN

Product Characteristics Color PINK Score no score Shape ROUND Size 6mm Flavor Imprint Code TV;075 Contains

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA204061 07/25/2013

Part 3 of 4 LEVONORGESTREL/ETHINYL ESTRADIOL  levonorgestrel/ethinyl estradiol tablet, film coated

Product Information Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LEVONORGESTREL (LEVONORGESTREL) LEVONORGESTREL 0.15 mg ETHINYL ESTRADIOL (ETHINYL ESTRADIOL) ETHINYL ESTRADIOL 0.03 mg

Inactive Ingredients Ingredient Name Strength ANHYDROUS LACTOSE   D&C RED NO. 27   FD&C BLUE NO. 1   HYPROMELLOSE 2208 (3 MPA.S)   HYPROMELLOSE, UNSPECIFIED   LACTOSE MONOHYDRATE   MICROCRYSTALLINE CELLULOSE   MAGNESIUM STEARATE   POLYETHYLENE GLYCOL, UNSPECIFIED   TITANIUM DIOXIDE   TRIACETIN

Product Characteristics Color PURPLE Score no score Shape ROUND Size 6mm Flavor Imprint Code TV;074 Contains

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA204061 07/25/2013

Part 4 of 4 ETHINYL ESTRADIOL  ethinyl estradiol tablet, film coated

Product Information Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ETHINYL ESTRADIOL (ETHINYL ESTRADIOL) ETHINYL ESTRADIOL 0.01 mg

Inactive Ingredients Ingredient Name Strength ANHYDROUS LACTOSE   D&C YELLOW NO. 10   FD&C YELLOW NO. 6   HYPROMELLOSE 2910 (3 MPA.S)   HYPROMELLOSE 2910 (6 MPA.S)   MAGNESIUM STEARATE   MICROCRYSTALLINE CELLULOSE   POLACRILIN POTASSIUM   POLYETHYLENE GLYCOL 400   POLYSORBATE 80   TITANIUM DIOXIDE

Product Characteristics Color YELLOW Score no score Shape ROUND Size 6mm Flavor Imprint Code TV;077 Contains

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA204061 07/25/2013

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA204061 07/25/2013

Labeler - Teva Women's Health, Inc. (017038951)

Revised: 08/2017   Teva Women's Health, Inc.