Lessina

Lessina is a prescription birth control medication used to prevent pregnancy. Lessina contains two hormones, levonorgestrel and ethinyl estradiol, which belong to a group of drugs called hormonal contraceptives. These hormones prevent pregnancy by stopping ovulation and by altering cervical mucus and the lining of the uterus to prevent sperm from entering.

This medication comes in tablet form and is taken once daily, with or without food.

Common side effects of Lessina include nausea, breast tenderness, and vaginal bleeding between menstrual periods. 

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Each cycle of Lessina® 28 (levonorgestrel and ethinyl estradiol tablets USP) consists of 21 pink active tablets each containing 0.1 mg levonorgestrel, USP and 0.02 mg ethinyl estradiol, USP; and seven white inert tablets. The inactive ingredients include anhydrous lactose, FD&C red no. 40 aluminum lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, corn starch, and titanium dioxide. Each white tablet contains only inert ingredients as follows: anhydrous lactose, hypromellose, microcrystalline cellulose, and magnesium stearate.

The structural formulas are as follows:

Levonorgestrel, USP

C21H28O2 Molecular Weight: 312.4

Ethinyl Estradiol, USP

C20H24O2 Molecular Weight: 296.4

Absorption

No specific investigation of the absolute bioavailability of levonorgestrel and ethinyl estradiol tablets in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration and is not subject to first-pass metabolism. Ethinyl estradiol is rapidly and almost completely absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, the absolute bioavailability of ethinyl estradiol is about 40%. After a single dose of three levonorgestrel and ethinyl estradiol tablets to 17 women under fasting conditions, the extents of absorption of levonorgestrel and ethinyl estradiol were 98.6% and 99%, respectively, relative to the same dose of the 2 drugs when given as a microcrystalline suspension in water. The effect of food on the bioavailability of levonorgestrel and ethinyl estradiol tablets following oral administration has not been evaluated.

The pharmacokinetics of levonorgestrel and ethinyl estradiol following daily administration of levonorgestrel and ethinyl estradiol tablets for 21 days per cycle for three cycles, were determined in 18 women. Estimates of the pharmacokinetic parameters of levonorgestrel and ethinyl estradiol following single and multiple dose administration of levonorgestrel and ethinyl estradiol tablets are summarized in Table I. Mean levonorgestrel and ethinyl estradiol levels after a single dose and on day 21 at steady state are shown in Figure I.

The pharmacokinetics of total levonorgestrel are non-linear due to an increase in binding to SHBG, which is attributed to increased SHBG levels that are induced by the daily administration of ethinyl estradiol. Increased binding of levonorgestrel to SHBG leads to decreased clearance of levonorgestrel. Observed maximum levonorgestrel concentrations increased from day 1 to day 21 of the 1st and 3rd cycles by 66% and 83%, respectively.

Figure I

In calculating the mean concentration for ethinyl estradiol, any individual subject value below the quantifiable limit (i.e., 20 pg/mL) was converted to 0; and the 0 values were included for calculation of the mean concentration.

Table I provides a summary of levonorgestrel and ethinyl estradiol pharmacokinetic parameters.

TABLE I MEAN (SD) PHARMACOKINETIC PARAMETERS OF LEVONORGESTREL AND ETHINYL ESTRADIOL TABLETS AFTER SINGLE DOSE AND AFTER MULTIPLE DOSING FOR 3 CYCLES

Levonorgestrel

Day (cycle)	Cmax ng/mL	tmax h	AUC ng·h/mL	CL/F mL/min/kg	Vz L	SHBG nmol/L
1	2.36(0.79)	1.3(0.4)	29.2(10)	1(0.3)	129(46)	64.5(22)
			AUC(0 to 24h) ng·h/mL
21(1)	4.04(2.08)	1(0.3)	43.8(22.4)	0.73(0.34)	106(42)	94.7(37.4)
21(3)	4.53(1.94)	1(0.3)	49.5(24.5)	0.65(0.33)	96(35)	107.4(45.8)

Ethinyl Estradiol

Day (cycle)	Cmax pg/mL	tmax h	AUC(0 to 24h) pg·h/ml
1	49.5(13.4)	1.5(0.4)	298(215)
21(1)	66.2(29.5)	1.4(0.4)	596(494)
21(3)	58.1(19.3)	1.4(0.3)	417(289)

Cmax = maximum concentration

tmax = time to maximum concentration

AUC = area under the drug concentration curve from time 0 to infinity

CL/F = oral clearance

Vz = volume of distribution

SHBG = sex hormone binding globulin

AUC(0 to 24) = area under the drug concentration time curve from time 0 to 24 hours; this represents the area for one dosing interval at steady state.

Distribution

Levonorgestrel in serum is primarily bound to SHBG. Protein binding values for levonorgestrel are provided in Table II. Ethinyl estradiol is about 97% bound to plasma albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis.

TABLE II.

Protein binding (mean ± SD) of levonorgestrel in pools of serum samples collected from 18 women after a single dose of levonorgestrel and ethinyl estradiol tablets, and following administration (once daily) over 3x21 days.

Parameter	Single Dose	Cycle 2	Cycle 4
% free	1.11(0.27)	0.79(0.22)	0.80(0.23)
% SHBG-bound	64.5(8.54)	75.6(6.59)	74.7(7.89)
% albumin-bound	34.4(8.28)	23.6(6.41)	24.5(7.67)

Metabolism

Levonorgestrel

The most important metabolic pathway occurs in the reduction of the Δ4-3-oxo group and hydroxylation at positions 2α, 1ß, and 16ß, followed by conjugation. Most of the metabolites that circulate in the blood are sulfates of 3α, 5ß-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent levonorgestrel also circulates as 17ß-sulfate. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation in levonorgestrel concentrations among users.

Ethinyl estradiol

Cytochrome P450 enzymes (CYP3A4) in the liver are responsible for the 2-hydroxylation that is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal excretion. Levels of Cytochrome P450 (CYP3A) vary widely among individuals and can explain the variation in the rates of ethinyl estradiol 2-hydroxylation. Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic circulation.

Excretion

The elimination half-life for levonorgestrel after a single dose of levonorgestrel and ethinyl estradiol tablets is 25.4 ± 9.7 hours. Levonorgestrel and its metabolites are primarily excreted in the urine. The elimination half-life of ethinyl estradiol has been reported to be between 15 and 25 hours.

See “Patient Labeling” printed below.

To achieve maximum contraceptive effectiveness, Lessina® (levonorgestrel and ethinyl estradiol tablets USP) must be taken exactly as directed at intervals not exceeding 24-hours.

Lessina Tablets are a monophasic preparation plus 7 inert tablets. The dosage of Lessina Tablets is one tablet daily for 21 consecutive days per menstrual cycle plus 7 white inert tablets according to the prescribed schedule. It is recommended that Lessina Tablets be taken at the same time each day, preferably after the evening meal or at bedtime. During the first cycle of medication, the patient should be instructed to take one pink Lessina Tablet daily and then 7 white inert tablets for twenty-eight (28) consecutive days, beginning on day one (1) of her menstrual cycle. (The first day of menstruation is day one.) Withdrawal bleeding usually occurs within 3 days following the last pink tablet. (If Lessina Tablets are first taken later than the first day of the first menstrual cycle of medication or postpartum, contraceptive reliance should not be placed on Lessina Tablets until after the first 7 consecutive days of administration. The possibility of ovulation and conception prior to initiation of medication should be considered.)

When switching from another oral contraceptive, Lessina Tablets should be started on the first day of bleeding following the last active tablet taken of the previous oral contraceptive.

The patient begins her next and all subsequent 28-day courses of Lessina Tablets on the same day of the week that she began her first course, following the same schedule. She begins taking her pink tablets on the next day after ingestion of the last white tablet, regardless of whether or not a menstrual period has occurred or is still in progress. Anytime a subsequent cycle of Lessina Tablets is started later than the next day, the patient should be protected by another means of contraception until she has taken a tablet daily for seven consecutive days.

If spotting or breakthrough bleeding occurs, the patient is instructed to continue on the same regimen. This type of bleeding is usually transient and without significance, however, if the bleeding is persistent or prolonged, the patient is advised to consult her physician. Although the occurrence of pregnancy is highly unlikely if Lessina Tablets are taken according to directions, if withdrawal bleeding does not occur, the possibility of pregnancy must be considered. If the patient has not adhered to the prescribed schedule (missed one or more active tablets or started taking them on a day later than she should have), the probability of pregnancy should be considered at the time of the first missed period and appropriate diagnostic measures taken before the medication is resumed. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen.

The risk of pregnancy increases with each active (pink) tablet missed. For additional patient instructions regarding missed pills, see the “WHAT TO DO IF YOU MISS PILLS” section in the DETAILED PATIENT LABELING below. If breakthrough bleeding occurs following missed tablets, it will usually be transient and of no consequence. If the patient misses one or more white tablets, she is still protected against pregnancy provided she begins taking pink tablets again on the proper day.

In the nonlactating mother, Lessina Tablets may be initiated postpartum, for contraception. When the tablets are administered in the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered. (See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS concerning thromboembolic disease.) It is to be noted that early resumption of ovulation may occur if bromocriptine mesylate has been used for the prevention of lactation.

Lessina® (levonorgestrel and ethinyl estradiol tablets USP 0.1 mg/ 0.02 mg) are packaged in blister cards. Each card contains 21 pink, round, film-coated, biconvex, unscored tablets, debossed stylized b on one side and 965 on the other side, and 7 white, round, biconvex, unscored tablets, debossed stylized b on one side and 208 on the other side.

Available in cartons of 3 blister cards (NDC: 0555-9014-67).

Store at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature].

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. B 4/2017

This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Oral contraceptives, also known as “birth-control pills” or “the pill”, are taken to prevent pregnancy, and when taken correctly, have a failure rate of less than 1% per year when used without missing any pills. The typical failure rate of large numbers of pill users is less than 3% per year when women who miss pills are included. For most women oral contraceptives are also free of serious or unpleasant side effects. However, forgetting to take pills considerably increases the chances of pregnancy.

For the majority of women, oral contraceptives can be taken safely. But there are some women who are at high risk of developing certain serious diseases that can be life-threatening or may cause temporary or permanent disability or death. The risks associated with taking oral contraceptives increase significantly if you:

• smoke • have high blood pressure, diabetes, high cholesterol • have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice, or malignant or benign liver tumors.

You should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding.

Cigarette smoking increases the risk of serious adverse effects on the heart and blood vessels from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should not smoke.

Most side effects of the pill are not serious. The most common such effects are nausea, vomiting, bleeding between menstrual periods, weight gain, breast tenderness, and difficulty wearing contact lenses. These side effects, especially nausea and vomiting may subside within the first three months of use.

The serious side effects of the pill occur very infrequently, especially if you are in good health and are young. However, you should know that the following medical conditions have been associated with or made worse by the pill:

1. Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), stoppage or rupture of a blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack and angina pectoris) or other organs of the body. As mentioned above, smoking increases the risk of heart attacks and strokes and subsequent serious medical consequences. 2. Liver tumors, which may rupture and cause severe bleeding. A possible but not definite association has been found with the pill and liver cancer. However, liver cancers are extremely rare. The chance of developing liver cancer from using the pill is thus even rarer. 3. High blood pressure, although blood pressure usually returns to normal when the pill is stopped.

The symptoms associated with these serious side effects are discussed in the detailed leaflet given to you with your supply of pills. Notify your doctor or healthcare provider if you notice any unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, as well as some anticonvulsants and some antibiotics, may decrease oral contraceptive effectiveness.

Studies to date of women taking the pill have not shown an increase in the incidence of cancer of the breast or cervix. There is, however, insufficient evidence to rule out the possibility that pills may cause such cancers.

Taking the pill provides some important non-contraceptive benefits. These include less painful menstruation, less menstrual blood loss and anemia, fewer pelvic infections, and fewer cancers of the ovary and the lining of the uterus.

Be sure to discuss any medical condition you may have with your healthcare provider. Your healthcare provider will take a medical and family history before prescribing oral contraceptives and will examine you. The physical examination may be delayed to another time if you request it and the healthcare provider believes that it is appropriate to postpone it. You should be reexamined at least once a year while taking oral contraceptives. The detailed patient information booklet gives you further information which you should read and discuss with your healthcare provider.

This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.

INSTRUCTIONS TO PATIENTS

HOW TO TAKE THE PILL

IMPORTANT POINTS TO REMEMBER

BEFORE YOU START TAKING YOUR PILLS:

1. BE SURE TO READ THESE DIRECTIONS:
Before you start taking your pills.
Anytime you are not sure what to do. 2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME.
If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. 3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1 to 3 PACKS OF PILLS.
If you do feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it does not go away, check with your doctor or clinic. 4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills.
On the days you take two pills, to make up for missed pills, you could also feel a little sick to your stomach. 5. IF YOU HAVE VOMITING OR DIARRHEA, for any reason, or IF YOU TAKE SOME MEDICINES, including some antibiotics, your pills may not work as well.
Use a back-up method (such as condoms, foam, or sponge) until you check with your doctor or clinic. 6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your doctor or clinic about how to make pill-taking easier or about using another method of birth control. 7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your doctor or clinic.

BEFORE YOU START TAKING YOUR PILLS

1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.
It is important to take it at about the same time every day. 2. LOOK AT YOUR PILL PACK TO SEE IF IT HAS 28 PILLS:
The pill pack has 21 (pink) “active” pills (with hormones) to take for three weeks, followed by 1 week of reminder pills (white) (without hormones).
Refer to the sample of the blister card below: 3. ALSO FIND:
1) where on the pack to start taking pills,
2) in what order to take the pills 4. BE SURE YOU HAVE READY AT ALL TIMES:
ANOTHER KIND OF BIRTH CONTROL (such as condoms, foam or sponge) to use as a back-up in case you miss pills.
AN EXTRA, FULL PILL PACK

WHEN TO START THE FIRST PACK OF PILLS

You have a choice for which day to start taking your first pack of pills. Decide with your doctor or clinic which is the best day for you. Pick a time of day which will be easy to remember.

DAY 1 START:

1. Take the first (pink) “active” pill of the first pack during the first 24 hours of your period. 2. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period.

SUNDAY START:

1. Take the first (pink) “active” pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day. 2. Use another method of birth control as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). Condoms, foam, or the sponge are good back-up methods of birth control.

WHAT TO DO DURING THE MONTH

1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY
Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea).
Do not skip pills even if you do not have sex very often. 2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS:
Start the next pack on the day after your last (white) “reminder” pill. Do not wait any days between packs.

WHAT TO DO IF YOU MISS PILLS

If you MISS 1 (pink) “active” pill:

1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take two pills in one day. 2. You do not need to use a back-up birth control method if you have sex.

If you MISS 2 (pink) “active” pills in a row in WEEK 1 OR WEEK 2 of your pack:

1. Take two pills on the day you remember and two pills the next day. 2. Then take one pill a day until you finish the pack. 3. You MAY BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms, foam, or sponge) as a back-up for those 7 days.

If you MISS 2 (pink) “active” pills in a row in THE 3rd WEEK:

1. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
If you are a Sunday Starter:
Keep taking one pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month but this is expected. However, if you miss your period two months in a row, call your doctor or clinic because you might be pregnant. 3. You MAY BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms, foam, or sponge) as a back-up for those 7 days.

If you MISS 3 OR MORE (pink) “active” pills in a row (during the first 3 weeks):

1. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
If you are a Sunday Starter:
Keep taking one pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month but this is expected. However, if you miss your period two months in a row, call your doctor or clinic because you might be pregnant. 3. You MAY BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms, foam, or sponge) as a back-up for those 7 days.

A REMINDER FOR THOSE ON 28-DAY PACKS:

If you forget any of the 7 (white) “reminder” pills in Week 4:

THROW AWAY the pills you missed.

Keep taking one pill each day until the pack is empty.

You do not need a back-up method.

FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED:

Use a BACK-UP METHOD anytime you have sex.

KEEP TAKING ONE ACTIVE PILL EACH DAY until you can reach your doctor or clinic.

Store at 20° to 25°C (68° to 77°F).

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.