Professional Information — Sronyx

Indications and Usage

Oral contraceptives are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception.

Oral contraceptives are highly effective. Table III lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

Dosage and Administration

Sronyx ^®(Levonorgestrel and Ethinyl Estradiol Tablets USP)

To achieve maximum contraceptive effectiveness, Sronyx must be taken exactly as directed at intervals not exceeding 24-hours.

Sronyx is a monophasic preparation plus 7 inert tablets. The dosage of Sronyx is one tablet daily for 21 consecutive days per menstrual cycle plus 7 peach inert tablets according to the prescribed schedule. It is recommended that Sronyx 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 white Sronyx tablet daily and then 7 peach 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 white tablet. (If Sronyx is first taken later than the first day of the first menstrual cycle of medication or postpartum, contraceptive reliance should not be placed on Sronyx 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, Sronyx 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 Sronyx on the same day of the week that she began her first course, following the same schedule. She begins taking her white tablets on the next day after ingestion of the last peach tablet, regardless of whether or not a menstrual period has occurred or is still in progress.

Anytime a subsequent cycle of Sronyx 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 Sronyx is 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 (white) tablet missed. For additional patient instructions regarding missed pills, see the "WHAT TO DO IF YOU MISS PILLS" section in the DETAILED PATIENT LABELINGbelow. If breakthrough bleeding occurs following missed tablets, it will usually be transient and of no consequence. If the patient misses one or more peach tablets, she is still protected against pregnancy provided she begins taking white tablets again on the proper day.

In the nonlactating mother, Sronyx 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.

Contraindications

Levonorgestrel and ethinyl estradiol tablets are contraindicated in females who are known to have or develop the following conditions:

• Thrombophlebitis or thromboembolic disorders
• A past history of deep-vein thrombophlebitis or thromboembolic disorders
• Cerebral-vascular or coronary-artery disease
• Current diagnosis of, or history of, breast cancer, which may be hormone sensitive
• Carcinoma of the endometrium or other known or suspected estrogen dependent neoplasia
• Undiagnosed abnormal genital bleeding
• Cholestatic jaundice of pregnancy or jaundice with prior pill use
• Hepatic adenomas or carcinomas
• Known or suspected pregnancy
• Are receiving Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations (see Warnings, RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT).

Adverse Reactions

Post Marketing 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 approximate 1.4 with more than 8-10 years of COC use.

Figure 2: Risk of Breast Cancer with Combined Oral Contraceptive Use

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.

An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see " WARNINGS" section).

• Thrombophlebitis
• Arterial thromboembolism
• Pulmonary embolism
• Myocardial infarction
• Cerebral hemorrhage
• Cerebral thrombosis
• Hypertension
• Gallbladder disease
• Hepatic adenomas or benign liver tumors

There is evidence of an association between the following conditions and the use of oral contraceptives, although additional confirmatory studies are needed:

• Mesenteric thrombosis
• Retinal thrombosis

The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug related:

• Nausea
• Vomiting
• Gastrointestinal symptoms, (such as abdominal cramps and bloating)
• Breakthrough bleeding
• Spotting
• Change in menstrual flow
• Amenorrhea
• Temporary infertility after discontinuation of treatment
• Edema
• Melasma which may persist
• Breast changes: tenderness, enlargement, secretion
• Change in weight (increase or decrease)
• Change in cervical erosion and secretion
• Diminution in lactation when given immediately postpartum
• Cholestatic jaundice
• Migraine
• Rash (allergic)
• Mental depression
• Reduced tolerance to carbohydrates
• Vaginal candidiasis
• Change in corneal curvature (steepening)
• Intolerance to contact lenses

The following adverse reactions have been reported in users of oral contraceptives and the association has been neither confirmed nor refuted:

• Pre-menstrual syndrome
• Cataracts
• Optic neuritis
• Changes in appetite
• Cystitis-like syndrome
• Headache
• Nervousness
• Dizziness
• Hirsutism
• Loss of scalp hair
• Erythema multiforme
• Erythema nodosum
• Hemorrhagic eruption
• Vaginitis
• Porphyria
• Impaired renal function
• Hemolytic uremic syndrome
• Budd-Chiari syndrome
• Acne
• Changes in libido
• Colitis

Drug Interactions

Reduced efficacy and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin. A similar association, though less marked, has been suggested with barbiturates, phenylbutazone, phenytoin sodium, and possibly with griseofulvin, ampicillin and tetracyclines.

Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation

Do not co-administer Sronyx with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations (see Warnings, RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT).

Overdosage

Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females.

Description

Each cycle of Sronyx ^®(Levonorgestrel and Ethinyl Estradiol Tablets USP) consists of 21 white active tablets each containing 0.1 mg levonorgestrel and 0.02 mg ethinyl estradiol; and seven peach tablets – inert. The inactive ingredients are Croscarmellose Sodium NF, Lactose Monohydrate NF, Magnesium Stearate NF, Microcrystalline Cellulose (PH 102) NF, and Povidone (K29/32) NF. Each inactive, placebo tablet contains the following inactive ingredients: FD & C Yellow #6 Lake 35-42%, Lactose Anhydrous (DT Micro) NF, Lactose Monohydrate (200M) NF, Magnesium Stearate NF and Microcrystalline Cellulose NF.

Levonorgestrel has a molecular weight of 312.4 and a molecular formula of C ₂₁H ₂₈O ₂. Ethinyl estradiol has a molecular weight of 296.4 and a molecular formula of C ₂₀H ₂₄O ₂. The structural formulas are as follows:

Clinical Pharmacology

Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

PHARMACOKINETICS

Absorption

No specific investigation of the absolute bioavailability of levonorgestrel and ethinyl estradiol of Levonorgestrel and Ethinyl Estradiol Tablets USP 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 USP to 17 women under fasting conditions, the extents of absorption of levonorgestrel and ethinyl estradiol were 98.6% and 99.0%, 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 USP following oral administration has not been evaluated.

The pharmacokinetics of levonorgestrel and ethinyl estradiol following daily administration of Levonorgestrel and Ethinyl Estradiol Tablets USP 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 USP 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 1.

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.

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.

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.

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 USP 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.

SPECIAL POPULATIONS

Hepatic Insufficiency

No formal studies have evaluated the effect of hepatic disease on the disposition of Levonorgestrel and Ethinyl Estradiol Tablets USP. However, steroid hormones may be poorly metabolized in patients with impaired liver function.

Renal Insufficiency

No formal studies have evaluated the effect of renal disease on the disposition of Levonorgestrel and Ethinyl Estradiol Tablets USP.

Drug-Drug Interactions

Interactions between ethinyl estradiol and other drugs have been reported in the literature.

• Interactions with Absorption

Diarrhea may increase gastrointestinal motility and reduce hormone absorption. Similarly, any drug which reduces gut transit time may reduce hormone concentrations in the blood.

• Interactions with Metabolism

Gastrointestinal Wall

Sulfation of ethinyl estradiol has been shown to occur in the gastrointestinal wall. Therefore, drugs which act as competitive inhibitors for sulfation in the gastrointestinal wall may increase ethinyl estradiol bioavailability.

Hepatic metabolism

Interactions can occur with drugs that induce microsomal enzymes which can decrease ethinyl estradiol concentrations (e.g., rifampin, barbiturates, phenylbutazone, phenytoin, griseofulvin).

• Interference with Enterohepatic Circulation

Some clinical reports suggest that enteroheptic circulation of estrogens may decrease when certain antibiotic agents are given, which may reduce ethinyl estradiol concentrations (e.g., ampicillin, tetracycline).

• Interference in the Metabolism of Other Drugs

Ethinyl estradiol may interfere with the metabolism of other drugs by inhibiting hepatic microsomal enzymes or by inducing hepatic drug conjugation, particularly glucuronidation. Accordingly, plasma and tissue concentrations may either be increased or decreased, respectively (e.g., cyclosporin, theophylline).

How Supplied / Storage and Handling

Sronyx ^®is available in a 28 Tablet Dispenser, arranged in 3 rows of 7 active tablets and 1 row of inert tablets, as follows:

21 active tablets: white, round tablet debossed with "WATSON" on one side and "967" on the other side. 7 inert tablets: peach, round tablet debossed with "WATSON" on one side and "P1" on the other side.

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

Patient Counseling Information

See " Patient Labeling" printed below.