HOW SUPPLIED SECTION.


HOW SUPPLIED. DOLISHALE (90 mcg levonorgestrel and 20 mcg ethinyl estradiol) tablets are available in blister pack, arranged in rows of active tablets as follows:28 round, green biconvex tablets debossed with H1 on one side.DOLISHALE Tablets are available in the following packaging configurations:Carton of Blister Card of 28 Tablets NDC 50742-659-28Carton of Blister Cards of 28 Tablets Each NDC 50742-659-84Carton of Blister Cards of 28 Tablets Each NDC 50742-659-68Store at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature].References available upon request.Rx OnlyIss: 12/2020I0154Rev AManufactured for:Ingenus Pharmaceuticals, LLCOrlando, FL 32839-6408Product of China. Image.

INDICATIONS & USAGE SECTION.


INDICATIONS AND USAGE. DOLISHALE is indicated for the prevention of pregnancy in women who elect to use oral contraceptives as method of contraception. Oral contraceptives are highly effective for pregnancy prevention. Table lists the typical unintended pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and implants, depend upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates. Table 2: Percentage of Women Experiencing an Unintended Pregnancy During The First Year of Typical Use and The First Year of Perfect Use of Contraception and The Percentage Continuing Use at The End of the First Year. United States. of Women Experiencing an Unintended Pregnancy within the First Year of Use of Women Continuing Use at One Year3 Method (1) Typical Use1 (2) Perfect Use2 (3) (4) Chance4 85 85 Spermicides5 26 40 Periodic abstinence 25 63 Calendar Ovulation Method Sympto-Thermal6 Post-Ovulation Cap7 Parous Women 40 26 42 Nulliparous Women 20 56 Sponge Parous Women 40 20 42 Nulliparous Women 20 56 Diaphragm7 20 56 Withdrawal 19 Condom8 Female (Reality(TM)) 21 56 Male 14 61 Pill 71 Progestin only 0.5 Combined 0.1 IUD Progesterone 2.0 1.5 81 Copper T380A 0.8 0.6 78 LNg 20 0.1 0.1 81 Depo-Provera(R) 0.3 0.3 70 Levonorgestrel Implants (Norplant(R)) 0.05 0.05 88 Female Sterilization 0.5 0.5 100 Male Sterilization 0.15 0.10 100 Emergency Contraceptive Pills: The FDA has concluded that certain combined oral contraceptives containing ethinyl estradiol and norgestrel or levonorgestrel are safe and effective for use as postcoital emergency contraception. Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.9 Lactation Amenorrhea Method: LAM is highly effective, temporary method of contraception.10 Source: Trussell J. Contraceptive efficacy. In: Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowel D, Guest F. Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers; 1998.1. Among typical couples who initiate use of method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. 2. Among couples who initiate use of method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. 3. Among couples attempting to avoid pregnancy, the percentage who continue to use method for one year. 4. The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether. 5. Foams, creams, gels, vaginal suppositories, and vaginal film. 6. Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. 7. With spermicidal cream or jelly. 8. Without spermicides. 9. The treatment schedule is one dose within 72 hours after unprotected intercourse, and second dose 12 hours after the first dose. The FDA has declared the following dosage regimens of oral contraceptives to be safe and effective for emergency contraception: for tablets containing 50 mcg of ethinyl estradiol and 500 mcg of norgestrel dose is tablets; for tablets containing 20 mcg of ethinyl estradiol and 100 mcg of levonorgestrel dose is tablets; for tablets containing 30 mcg of ethinyl estradiol and 150 mcg of levonorgestrel dose is tablets. 10. However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches months of age.

OVERDOSAGE SECTION.


OVERDOSAGE. Symptoms of oral contraceptive overdosage in adults and children may include nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue; withdrawal bleeding may occur in females. There is no specific antidote and further treatment of overdose, if necessary, is directed to the symptoms.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL 1-cycle carton. 1-cycle carton.

PHARMACOKINETICS SECTION.


Pharmacokinetics. 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 (bioavailability about 100%) 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 bioavailability of ethinyl estradiol is between 38% and 48%. summary of the single dose and multiple dose levonorgestrel and ethinyl estradiol pharmacokinetic parameters for 18 women under fasting conditions is provided in Table 1. The plasma concentrations of levonorgestrel and ethinyl estradiol reached steady-state by approximately day 14. Levonorgestrel and ethinyl estradiol concentrations did not increase from days 14 to 28, but did increase from days to 28.Table 1: Mean (SD) Pharmacokinetic Parameters of Levonorgestrel and Ethinyl Estradiol Tablets Over 28-Day Dosing Period LNG Day Cmax (ng/mL) Tmax (h) t1/2 (h) AUC0-24 (ngoh/mL) 2.4 (0.9) 1.2 (0.4) 16 (8) 14 5.4 (2.1) 1.7 (1.4) 68 (36) 28 5.7 (2.1) 1.3 (0.8) 36 (19) 74 (41) EE Day (pg/mL) (h) (h) (pg h/mL) 47.7 (20.1) 1.3 (0.5) 378 (140) 14 72.7 (37.2) 1.4 (0.5) 695 (361) 28 74.4 (29.7) 1.4 (0.5) 21 (7) 717 (351) The mean plasma concentrations of levonorgestrel and ethinyl estradiol following single (day 1) and multiple (days 14 and 28) oral administrations of levonorgestrel 90 mcg in combination with ethinyl estradiol 20 mcg to 18 healthy women is provided in Figure 1. Figure 1: Mean Plasma +- SD+Concentrations of Levonorgestrel and Ethinyl Estradiol Following Single (Day 1) and Multiple (Days 14 and 28) Oral Administrations of Levonorgestrel 90 mcg in Combination with Ethinyl Estradiol 20 mcg to Healthy WomenThe effect of food on the rate and the extent of levonorgestrel and ethinyl estradiol absorption following oral administration of DOLISHALE has not been evaluated.Distribution Levonorgestrel in serum is primarily bound to sex hormone-binding globulin (SHBG). Ethinyl estradiol is about 97% bound to serum albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis. Metabolism Levonorgestrel: The most important metabolic pathways are reduction of the 4-3-oxo group and hydroxylation at positions 2, 1, and 16, followed by conjugation. Most of the circulating metabolites are sulfates of 3, 5-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent levonorgestrel also circulates as 17-sulfate. 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.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, sulfation, and glucuronidation prior to urinary and fecal excretion. Levels of CYP3A4 vary widely among individuals and can explain the variation in rates of ethinyl estradiol 2-hydroxylation. Excretion The terminal elimination half-life for levonorgestrel in levonorgestrel and ethinyl estradiol tablets is about 36 hours. Levonorgestrel and its metabolites are excreted in the urine (40% to 68%) and in feces (16% to 48%). The terminal elimination half-life of ethinyl estradiol in levonorgestrel and ethinyl estradiol tablets is about 21 hours. Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic recirculation.

PRECAUTIONS SECTION.


PRECAUTIONS. This product contains FD&C Yellow No. (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.. 1. General. Patients should be counseled that oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. Scheduled withdrawal bleeding does not occur with the use of DOLISHALE, therefore, the absence of withdrawal bleeding cannot be used as sign of an unexpected pregnancy and as such, unexpected pregnancy may be difficult to recognize. Although pregnancy is unlikely if DOLISHALE is taken as directed, if for any reason, pregnancy is suspected in woman using DOLISHALE, pregnancy test should be performed.. 2. Physical Examination and Follow-Up. periodic personal and family medical history and complete physical examination are appropriate for all women, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen, and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent, or recurrent abnormal vaginal bleeding, appropriate diagnostic measures should be conducted to rule out malignancy. Women with strong family history of breast cancer or who have breast nodules should be monitored with particular care. 3. Lipid Disorders. Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. (See WARNINGS, 1a., 1d., and 9.) small proportion of women will have adverse lipid changes while taking oral contraceptives. Nonhormonal contraception should be considered in women with uncontrolled dyslipidemias. Persistent hypertriglyceridemia may occur in small population of combination oral contraceptive users. Elevations of plasma triglycerides may lead to pancreatitis and other complications. 4. Liver Function. If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function. 5. Fluid Retention. Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. 6. Emotional Disorders. Patients becoming significantly depressed while taking oral contraceptives should stop the medication and use an alternate method of contraception in an attempt to determine whether the symptom is drug related. Women with history of depression should be carefully observed and the drug discontinued if depression recurs to serious degree. 7. Contact Lenses. Contact-lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist. 8. Gastrointestinal. Diarrhea and/or vomiting may reduce hormone absorption resulting in decreased serum concentrations.. 9. Drug Interactions. Changes in Contraceptive Effectiveness Associated with Coadministration of Other Products: Contraceptive effectiveness may be reduced when hormonal contraceptives are coadministered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or unscheduled bleeding. Examples include rifampin, rifabutin, barbiturates, primidone, phenylbutazone, phenytoin, dexamethasone, carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin, and modafinil. In such cases nonhormonal back-up method of birth control should be considered. Several cases of contraceptive failure and unscheduled bleeding have been reported in the literature with concomitant administration of antibiotics such as ampicillin and other penicillins, and tetracyclines. However, clinical pharmacology studies investigating drug interactions between combined oral contraceptives and these antibiotics have reported inconsistent results. Enterohepatic recirculation of estrogens may also be decreased by substances that reduce gut transit time. Several of the anti-HIV protease inhibitors have been studied with coadministration of oral combination hormonal contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. The safety and efficacy of oral contraceptive products may be affected with coadministration of anti-HIV protease inhibitors. Health care professionals should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information. Concomitant Use with HCV Combination Therapy Liver Enzyme Elevation Do not co-administer DOLISHALE 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 TREATMENT).Herbal products containing St. Johns Wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in unscheduled bleeding. Increase in Plasma Levels Associated with Coadministered Drugs: Coadministration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increases AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen increase the bioavailability of ethinyl estradiol since these drugs act as competitive inhibitors for sulfation of ethinyl estradiol in the gastrointestinal wall, known pathway of elimination for ethinyl estradiol. CYP 3A4 inhibitors such as indinavir, itraconazole, ketoconazole, fluconazole, and troleandomycin may increase plasma hormone levels. Troleandomycin may also increase the risk of intrahepatic cholestasis during coadministration with combination oral contraceptives. Changes in Plasma Levels of Coadministered Drugs: Combination hormonal contraceptives containing some synthetic estrogens (eg, ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone and other corticosteroids, and theophylline have been reported with concomitant administration of oral contraceptives. Decreased plasma concentrations of acetaminophen and lamotrigine, and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid, due to induction of conjugation (particularly glucuronidation), have been noted when these drugs were administered with oral contraceptives.The prescribing information of concomitant medications should be consulted to identify potential interactions. 10. Interactions with Laboratory Tests. Certain endocrine- and liver-function tests and blood components may be affected by oral contraceptives: a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability. b. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered. c. Other binding proteins may be elevated in serum ie, corticosteroid binding globulin (CBG), sex hormone-binding globulins (SHBG) leading to increased levels of total circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. d. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected. e. Glucose tolerance may be decreased. f. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if woman becomes pregnant shortly after discontinuing oral contraceptives. 11. Carcinogenesis. See WARNINGS section. 12. Pregnancy. Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS sections. 13. Nursing Mothers. Small amounts of oral contraceptive steroids and/or metabolites have been identified in the milk of nursing mothers, and few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, combination oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use combination oral contraceptives, but to use other forms of contraception until she has completely weaned her child. 14. Pediatric Use. Safety and efficacy of levonorgestrel and ethinyl estradiol tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.. 15. Geriatric Use. This product has not been studied in women over 65 years of age and is not indicated in this population. 16. Information for the Patient. See DETAILED PATIENT LABELING printed below.

SPL UNCLASSIFIED SECTION.


Patients should be counseled that oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.

ADVERSE REACTIONS SECTION.


ADVERSE REACTIONS. An increased risk of the following serious adverse reactions (see WARNINGS section for additional information) has been associated with the use of oral contraceptives: Thromboembolic and thrombotic disorders and other vascular problems (including thrombophlebitis and venous thrombosis with or without pulmonary embolism, mesenteric thrombosis, arterial thromboembolism, myocardial infarction, cerebral hemorrhage, cerebral thrombosis, transient ischemic attack), carcinoma of the reproductive organs and breasts, hepatic neoplasia/liver disease (including hepatic adenomas or benign liver tumors), ocular lesions (including retinal vascular thrombosis), gallbladder disease, carbohydrate and lipid effects, elevated blood pressure, and headache including migraine. The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug related (alphabetically listed): Acne Amenorrhea Anaphylactic/anaphylactoid reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms Breast changes: tenderness, pain, enlargement, secretion Budd-Chiari syndrome Cervical erosion and secretion, change in Cholestatic jaundice Chorea, exacerbation of Colitis Contact lenses, intolerance to Corneal curvature (steepening), change in Dizziness Edema/fluid retention Erythema multiforme Erythema nodosum Focal nodular hyperplasia Gastrointestinal symptoms (such as abdominal pain, cramps, and bloating) Hirsutism Infertility after discontinuation of treatment, temporary Lactation, diminution in, when given immediately postpartum Libido, change in Melasma/chloasma which may persist Menstrual flow, change in Mood changes, including depressiono Nausea Nervousness Pancreatitis Porphyria, exacerbation of Rash (allergic) Scalp hair, loss of Serum folate levels, decrease in Spotting Systemic lupus erythematosus, exacerbation of Unscheduled bleeding Vaginitis, including candidiasis Varicose veins, aggravation of Vomiting Weight or appetite (increase or decrease), change in The following adverse reactions have been reported in users of oral contraceptives: Cataracts Cystitis-like syndrome Dysmenorrhea Hemolytic uremic syndrome Hemorrhagic eruption Optic neuritis, which may lead to partial or complete loss of vision Premenstrual syndrome Renal function, impaired To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals, LLC Toll-Free at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

BOXED WARNING SECTION.


Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with the extent of smoking (in epidemiologic studies, 15 or more cigarettes per day was associated with significantly increased risk) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.

CLINICAL PHARMACOLOGY SECTION.


CLINICAL PHARMACOLOGY. Mode of Action. 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 tablets in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability about 100%) 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 bioavailability of ethinyl estradiol is between 38% and 48%. summary of the single dose and multiple dose levonorgestrel and ethinyl estradiol pharmacokinetic parameters for 18 women under fasting conditions is provided in Table 1. The plasma concentrations of levonorgestrel and ethinyl estradiol reached steady-state by approximately day 14. Levonorgestrel and ethinyl estradiol concentrations did not increase from days 14 to 28, but did increase from days to 28.Table 1: Mean (SD) Pharmacokinetic Parameters of Levonorgestrel and Ethinyl Estradiol Tablets Over 28-Day Dosing Period LNG Day Cmax (ng/mL) Tmax (h) t1/2 (h) AUC0-24 (ngoh/mL) 2.4 (0.9) 1.2 (0.4) 16 (8) 14 5.4 (2.1) 1.7 (1.4) 68 (36) 28 5.7 (2.1) 1.3 (0.8) 36 (19) 74 (41) EE Day (pg/mL) (h) (h) (pg h/mL) 47.7 (20.1) 1.3 (0.5) 378 (140) 14 72.7 (37.2) 1.4 (0.5) 695 (361) 28 74.4 (29.7) 1.4 (0.5) 21 (7) 717 (351) The mean plasma concentrations of levonorgestrel and ethinyl estradiol following single (day 1) and multiple (days 14 and 28) oral administrations of levonorgestrel 90 mcg in combination with ethinyl estradiol 20 mcg to 18 healthy women is provided in Figure 1. Figure 1: Mean Plasma +- SD+Concentrations of Levonorgestrel and Ethinyl Estradiol Following Single (Day 1) and Multiple (Days 14 and 28) Oral Administrations of Levonorgestrel 90 mcg in Combination with Ethinyl Estradiol 20 mcg to Healthy WomenThe effect of food on the rate and the extent of levonorgestrel and ethinyl estradiol absorption following oral administration of DOLISHALE has not been evaluated.Distribution Levonorgestrel in serum is primarily bound to sex hormone-binding globulin (SHBG). Ethinyl estradiol is about 97% bound to serum albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis. Metabolism Levonorgestrel: The most important metabolic pathways are reduction of the 4-3-oxo group and hydroxylation at positions 2, 1, and 16, followed by conjugation. Most of the circulating metabolites are sulfates of 3, 5-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent levonorgestrel also circulates as 17-sulfate. 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.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, sulfation, and glucuronidation prior to urinary and fecal excretion. Levels of CYP3A4 vary widely among individuals and can explain the variation in rates of ethinyl estradiol 2-hydroxylation. Excretion The terminal elimination half-life for levonorgestrel in levonorgestrel and ethinyl estradiol tablets is about 36 hours. Levonorgestrel and its metabolites are excreted in the urine (40% to 68%) and in feces (16% to 48%). The terminal elimination half-life of ethinyl estradiol in levonorgestrel and ethinyl estradiol tablets is about 21 hours. Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic recirculation. Special Populations. Race No formal studies on the effect of race on the pharmacokinetic parameters of levonorgestrel and ethinyl estradiol tablets were conducted. Hepatic Insufficiency No formal studies have evaluated the effect of hepatic disease on the disposition of levonorgestrel and ethinyl estradiol tablets. 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. Drug-Drug Interactions See PRECAUTIONS section Drug Interactions. Image.

CLINICAL STUDIES SECTION.


Clinical Studies. The efficacy and safety of levonorgestrel and ethinyl estradiol tablets were studied in one-year clinical trials of subjects age 18 to 49. There were no exclusions for body mass index (BMI), weight, or bleeding history. The primary efficacy and safety study (313-NULL) was one-year open-label clinical trial that treated 2,134 subjects in North America. Of these subjects 1,213 (56.8%) discontinued prematurely, including 102 (4.8%) discontinued by the Sponsor for early study closure. The mean weight of subjects in this study was 70.38 kg. The efficacy of levonorgestrel and ethinyl estradiol tablets was assessed by the number of pregnancies that occurred after the onset of treatment and within 14 days of the last dose. Among subjects 35 years or less, there were 23 pregnancies (4 of these occurred during the interval to 14 days after the last day of pill use) during 12,572 28-day pill packs of use. The resulting total Pearl Index was 2.38 (95% CI: 1.51, 3.57) and the one-year life table pregnancy rate was 2.39 (95% CI: 1.57, 3.62). Pill pack cycles during which subjects used back-up contraception or were not sexually active were not included in these calculations. Among women 35 years or less who took the pills completely as directed, there were 15 pregnancies (method failures) resulting in Pearl Index of 1.55 (95% CI: 0.87, 2.56) and the one-year life table pregnancy rate was 1.59 (95% CI: 0.95 to 2.67).In second supportive study conducted in Europe (315-EU), 641 subjects were randomized to levonorgestrel and ethinyl estradiol tablets (n=323) or the cyclic comparator of 100 mcg levonorgestrel and 20 mcg ethinyl estradiol (n=318). The mean weight of subjects in this study was 63.86 kg. The efficacy analysis among women 35 years or less included 2,756 levonorgestrel and ethinyl estradiol tablet pill packs and 2,886 cyclic comparator pill packs. There was one pregnancy in the levonorgestrel and ethinyl estradiol group that occurred within 14 days following the last dose. There were three pregnancies in the cyclic comparator group.

CONTRAINDICATIONS SECTION.


CONTRAINDICATIONS. Combination oral contraceptives should not be used in women with any of the following conditions: Thrombophlebitis or thromboembolic disorders History of deep-vein thrombophlebitis or thromboembolic disorders Cerebrovascular or coronary artery disease (current or past history) Valvular heart disease with thrombogenic complications Thrombogenic rhythm disorders Hereditary or acquired thrombophilias Major surgery with prolonged immobilization Diabetes with vascular involvement Headaches with focal neurological symptoms such as aura Uncontrolled hypertension Known or suspected carcinoma of the breast or personal history of breast cancer 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, or active liver disease Known or suspected pregnancy Hypersensitivity to any of the components of DOLISHALE Are receiving Hepatitis 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 TREATMENT).

DESCRIPTION SECTION.


DESCRIPTION. Twenty-eight (28) green tablets each containing 90 mcg of levonorgestrel (17)-(-)13-ethyl-17-hydroxy-18, 19-dinorpregn-4-en-20-yn-3-one, totally synthetic progestogen, and 20 mcg of ethinyl estradiol, (17)-19-norpregna-1,3,5(10)-trien-20-yne-3,17-diol. The inactive ingredients present are titanium dioxide, macrogol/PEG 3000 NF, talc, polyvinyl alcohol, lecithin (soya), FD&C Blue Aluminum Lake, FD&C Yellow Aluminum Lake, FD&C Red 40 Aluminum Lake, lactose monohydrate, magnesium stearate and pregelatinized starch.. Image.

DOSAGE & ADMINISTRATION SECTION.


DOSAGE AND ADMINISTRATION. To achieve maximum contraceptive effectiveness, DOLISHALE (levonorgestrel and ethinyl estradiol tablets) must be taken exactly as directed and at intervals not exceeding 24 hours. The possibility of ovulation and conception prior to initiation of medication should be considered. Women who do not wish to become pregnant after discontinuation should be advised to immediately use another method of birth control. The dosage of DOLISHALE is one green tablet daily without any tablet-free interval. It is recommended that DOLISHALE tablets be taken at the same time each day. Initiation of Therapy Instructions for beginning DOLISHALE are provided in Table below.Table Current contraceptive therapy DOLISHALE start day Nonhormonal back-up method of birth control needed when correctly starting DOLISHALE None Day of patients menstrual cycle (during the first 24 hours of her period) No 21-day COC regimen OR 28-day COC regimen Day of patients withdrawal bleed, at the latest days after her last active tablet. No Progestin-only pill Day after taking progestin-only pill Yes, for the first days of DOLISHALE tablet taking Implant Day of implant removal Yes, for the first days of DOLISHALE tablet taking Injection Day the next injection is due Yes, for the first days of DOLISHALE tablet taking If spotting or unscheduled 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 health care professional. The possibility of ovulation increases with each successive day that scheduled green tablets are missed. If the patient has not adhered to the prescribed schedule (missed one or more tablets or started taking them on day later than she should have), the probability of pregnancy should be considered. Hormonal contraception must be discontinued if pregnancy is confirmed. The risk of pregnancy increases with each tablet missed. For additional patient instructions regarding missed tablets, see the WHAT TO DO IF YOU MISS PILLS section in the DETAILED PATIENT LABELING below. DOLISHALE may be initiated no earlier than day 28 postpartum in the nonlactating mother or after second-trimester abortion due to the increased risk for thromboembolism (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS concerning thromboembolic disease). The patient should be advised to use nonhormonal back-up method for the first days of tablet-taking. However, if intercourse has already occurred, pregnancy should be excluded before the start of combined oral contraceptive use or the patient must wait for her first menstrual period. In the case of first-trimester abortion, if the patient starts DOLISHALE immediately, additional contraceptive measures are not needed.

WARNINGS SECTION.


WARNINGS. Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with the extent of smoking (in epidemiologic studies, 15 or more cigarettes per day was associated with significantly increased risk) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke. The use of oral contraceptives is associated with increased risks of several serious conditions including venous and arterial thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism, stroke, and transient ischemic attack), hepatic neoplasia, gallbladder disease, and hypertension, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as certain inherited or acquired thrombophilias, hypertension, hyperlipidemias, obesity, diabetes, and surgery or trauma with increased risk of thrombosis (see CONTRAINDICATIONS). Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks. The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher doses of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower doses of both estrogens and progestogens remains to be determined.Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide measure of the relative risk of disease, namely, ratio of the incidence of disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of disease. Cohort studies provide measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of disease in the population. For further information, the reader is referred to text on epidemiological methods. 1. Thromboembolic Disorders and Other Vascular Problems DOLISHALE is non-cyclic oral contraceptive that provides low daily dose of estrogen and progestin; however, DOLISHALE provides women with more hormonal exposure on yearly basis (13 additional weeks of hormone intake per year) than conventional cyclic oral contraceptives containing the same strength of synthetic estrogens and similar strength of progestins. a. Myocardial Infarction An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary-artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six. The risk is very low under the age of 30. Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarction in women in their mid-thirties or older with smoking accounting for the majority of excess cases. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 (Figure 3) among women who use oral contraceptives. Figure 3: Circulatory Disease Mortality Rates per 100,000 Woman Years by Age, Smoking Status and Oral Contraceptive Use Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age, and obesity. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create state of hyperinsulinism. Oral contraceptives have been shown to increase blood pressure among users (see section 10 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. b. Venous Thrombosis and Thromboembolism An increased risk of venous thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. The risk of venous thrombotic and thromboembolic events is further increased in women with conditions predisposing for venous thrombosis and thromboembolism. Case control studies have found the relative risk of users compared to non-users to be for the first episode of superficial venous thrombosis, to 11 for deep-vein thrombosis or pulmonary embolism, and 1.5 to for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about for new cases and about 4.5 for new cases requiring hospitalization. The approximate incidence of deep-vein thrombosis and pulmonary embolism in users of low dose (<0.05 mg ethinyl estradiol) combination oral contraceptives is up to per 10,000 woman-years compared to 0.5 to per 10,000 woman-years for non-users. However, the incidence is less than that associated with pregnancy (6 per 10,000 woman-years). The excess risk is highest during the first year woman ever uses combined oral contraceptive. Venous thromboembolism may be fatal. The risk of thromboembolic disease due to oral contraceptives is not related to length of use and gradually disappears after pill use is stopped. post-marketing observational study evaluated the risk of venous thromboembolism with levonorgestrel and ethinyl estradiol tablets use in two large US automated healthcare claims databases. The study was not completed as planned due to low accrual of levonorgestrel and ethinyl estradiol tablets users in these databases and discontinuation of the product from the market due to low usage. At study discontinuation, the crude incidence rate of venous thromboembolism among levonorgestrel and ethinyl estradiol tablets users (n=12,281) was 17.6 per 10,000 person- years, compared to 8.8 per 10,000 person-years among the users of cyclic oral contraceptives containing 20 mcg of ethinyl estradiol and progestogen, and 5.1 per 10,000 person-years among the users of cyclic oral contraceptives containing the progestin levonorgestrel and 20 mcg of ethinyl estradiol. Adjustment for important risk factors or confounders (such as obesity, cardiovascular disease and other diseases) for venous thromboembolism could not be performed due to the small sample size. Although the study results suggest an elevated risk of venous thromboembolism with current levonorgestrel and ethinyl estradiol tablets use compared to cyclic oral hormonal contraceptive use, reliable interpretation of the results is significantly limited due to the small sample size and concerns over unmeasured and uncontrolled confounding, as well as questions about the suitability of the comparator selection and the validity of the venous thromboembolism definition.A two-to-four fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate post-partum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breast-feed, or after midtrimester pregnancy termination. c. Cerebrovascular Diseases Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be risk factor for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes. Transient ischemic attacks have also been associated with oral contraceptive use. In large study, the relative risk of thrombotic strokes has been shown to range from for normotensive users to 14 for users with severe hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension. The attributable risk is also greater in older women. Oral contraceptives also increase the risk for stroke in women with other underlying risk factors such as certain inherited or acquired thrombophilias. Women with migraine (particularly migraine/headaches with focal neurological symptoms such as aura) who take combination oral contraceptives may be at an increased risk of stroke. (See CONTRAINDICATIONS.) d. Dose-Related Risk of Vascular Disease From Oral Contraceptives positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease. decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents. decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogen used in the contraceptive. The amount of both hormones should be considered in the choice of an oral contraceptive. Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest estrogen content which is judged appropriate for the individual patient. e. Persistence of Risk of Vascular Disease There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persisted for at least years for women 40 to 49 years who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups. In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least years after discontinuation of oral contraceptives, although excess risk was very small. However, both studies were performed with oral contraceptive formulations containing 0.05 mg or higher of estrogens. 2. Estimates of Mortality From Contraceptive Use One study gathered data from variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table 3). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is less than that associated with childbirth. The observation of possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970s -- but not reported until 1983. However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this labeling. Because of these changes in practice, and also because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy nonsmoking women (even with the newer low-dose formulations), there are greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception. Therefore, the Committee recommended that the benefits of oral contraceptive use by healthy nonsmoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective.Table 3: Annual Number of Birth-Related or Method-Related Deaths Associated with Control of Fertility per 100,000 Nonsterile Women, by Fertility-Control Method and According to Age Method of control and outcome 15 to 19 20 to 24 25 to 29 30 to 34 35 to 39 40 to 44 No fertility-control methods 7.0 7.4 9.1 14.8 25.7 28.2 Oral contraceptives nonsmoker 0.3 0.5 0.9 1.9 13.8 31.6 Oral contraceptives smoker 2.2 3.4 6.6 13.5 51.1 117.2 IUD 0.8 0.8 1.0 1.0 1.4 1.4 Condom 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/spermicide 1.9 1.2 1.2 1.3 2.2 2.8 Periodic abstinence 2.5 1.6 1.6 1.7 2.9 3.6 Deaths are birth-related Deaths are method-relatedAdapted from H.W. Ory, Family Planning Perspectives, 15:57 to 63, 1983.. 3. Carcinoma of the Reproductive Organs and Breasts Numerous epidemiological studies have examined the association between the use of oral contraceptives and the incidence of breast and cervical cancer. The risk of having breast cancer diagnosed may be slightly increased among current and recent users of combination oral contraceptives. However, this excess risk appears to decrease over time after combination oral contraceptive discontinuation and by 10 years after cessation the increased risk disappears. Some studies report an increased risk with duration of use while other studies do not and no consistent relationships have been found with dose or type of steroid. Some studies have reported small increase in risk for women who first use combination oral contraceptives at younger age. Most studies show similar pattern of risk with combination oral contraceptive use regardless of womans reproductive history or her family breast cancer history. Breast cancers diagnosed in current or previous oral contraceptive users tend to be less clinically advanced than in nonusers. Women with known or suspected carcinoma of the breast or personal history of breast cancer should not use oral contraceptives because breast cancer is usually hormonally sensitive tumor. Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia or invasive cervical cancer in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. In spite of many studies of the relationship between combination oral contraceptive use and breast and cervical cancers, cause-and-effect relationship has not been established. Endometrial biopsies performed in subset of subjects (Study 1; = 93) ages 18 to 49 years, after to 12 months of use of levonorgestrel and ethinyl estradiol, did not reveal any hyperplasias or malignancies. Endometrial malignancy is rare in this age group, so change in the risk is unlikely to be detected with study of this size. 4. Hepatic Neoplasia Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of these benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, risk that increases after four or more years of use. Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive user. However, these cancers are extremely rare in the U.S. and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users. 5. RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS TREATMENTDuring clinical trials with the Hepatitis combination drug regimen that contains ombitasvir/ paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 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 COCs. Discontinue DOLISHALE prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ ritonavir, with or without dasabuvir [see Contraindications (4)]. DOLISHALE can be restarted approximately weeks following completion of treatment with the combination drug regimen.. 6. Ocular Lesions There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives that may lead to partial or complete loss of vision. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately. 7. Oral Contraceptive Use Before or During Early Pregnancy Extensive epidemiological studies have revealed no increased risk of birth defects in infants born to women who have used oral contraceptives prior to pregnancy. Studies also do not suggest teratogenic effect, particularly insofar as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy (see CONTRAINDICATIONS section). The administration of oral contraceptives to induce withdrawal bleeding should not be used as test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion. The possibility of pregnancy should be considered in any patient who may be experiencing symptoms of pregnancy, especially if she has not adhered to the prescribed schedule. Oral-contraceptive use must be discontinued if pregnancy is confirmed. 8. Gallbladder Disease Combination oral contraceptives may worsen existing gallbladder disease and may accelerate the development of this disease in previously asymptomatic women. Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal. The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens. 9. Carbohydrate and Lipid Metabolic Effects Oral contraceptives have been shown to cause glucose intolerance in significant percentage of users. Oral contraceptives containing greater than 0.075 mg of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance. Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. However, in the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives. small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS, 1a. and 1d.; PRECAUTIONS, 3.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users. 10. Elevated Blood Pressure An increase in blood pressure has been reported in women taking oral contraceptives and this increase is more likely in older oral contraceptive users and with continued use. Data from the Royal College of General Practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing quantities of progestogens. Women with history of hypertension or hypertension-related diseases, or renal disease should be encouraged to use another method of contraception. If women with hypertension elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued (see CONTRAINDICATIONS section). For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension among ever- and never-users. 11. Headache The onset or exacerbation of migraine or development of headache with new pattern that is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause. (See WARNINGS, 1c. and CONTRAINDICATIONS.) 12. Bleeding Irregularities When prescribing DOLISHALE, the convenience of having no scheduled menstrual bleeding should be weighed against the inconvenience of unscheduled breakthrough bleeding and spotting. In Study 313-NULL, 385/2,134 (18%) of women discontinued prematurely due to bleeding that was reported either as an adverse event or where bleeding was given as one of the reasons for discontinuation (see INDICATIONS AND USAGE, Clinical Studies).Figure shows the percentage of levonorgestrel and ethinyl estradiol subjects in study 313-NULL by pill pack who experienced unscheduled bleeding or spotting only (Defined as No sanitary protection required). Figure shows the percentage of levonorgestrel and ethinyl estradiol tablet subjects with complete bleeding data in Study 313-NULL who had or more and or more days of bleeding and/or spotting during each pill pack cycle. During pill pack 2, 67% of subjects experienced or more days of bleeding and/or spotting and 54% of these subjects experienced or more days of bleeding and/or spotting. During the final cycle of use of levonorgestrel and ethinyl estradiol (pill pack 13), these percentages were 31% and 20%, respectively.As in any case of bleeding irregularities, nonhormonal causes should be considered and adequate diagnostic measures may be indicated to rule out pregnancy, infection, malignancy, or other conditions. Some women may encounter post-pill amenorrhea or oligomenorrhea (possibly with anovulation), especially when such condition was preexistent. 13. Ectopic Pregnancy Ectopic as well as intrauterine pregnancy may occur in contraceptive failures. Image. Image. Image.