Levonorgestrel and ethinyl estradiol tablets are indicated for use by females of reproductive potential to prevent pregnancy. Levonorgestrel and ethinyl estradiol tablet is a combination of levonorgestrel, a progestin, and ethinyl estradiol an estrogen indicated for use by females of reproductive potential to prevent pregnancy. ( 1 )
Contraindications
Levonorgestrel and Ethinyl Estradiol Tablets is contraindicated in females who are known to have or develop the following conditions: A high risk of arterial or venous thrombotic diseases. Examples include females who are known to: Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions ( 5.1 )] . Have current or history of deep vein thrombosis or pulmonary embolism [see Warnings and Precautions ( 5.1 )] .
Have cerebrovascular disease [see Warnings and Precautions ( 5.1 )] . Have coronary artery disease [see Warnings and Precautions ( 5.1 )] . Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions ( 5.1 )] Have inherited or acquired hypercoagulopathies [see Warnings and Precautions ( 5.1 )].
Have uncontrolled hypertension or hypertension with vascular disease [see Warnings and Precautions ( 5.4 )] . Have diabetes mellitus and are over age of 35, diabetes mellitus with hypertension or vascular disease or other end-organ damage, or diabetes mellitus of >20 years duration [see Warnings and Precautions ( 5.7 )] . Have headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches [ see Warnings and Precautions ( 5.8 ) ].
Current diagnosis of, or history of breast cancer, which may be hormone sensitive [see Warnings and Precautions ( 5.11 )]. Liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis [ see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.6 )]. Undiagnosed abnormal uterine bleeding [ see Warnings and Precautions ( 5.9 ) ]. Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [ see Warnings and Precautions ( 5.3 ) ].
A high risk of arterial or venous thrombotic diseases ( 4 ) Liver tumors or liver disease, acute viral hepatitis or decompensated cirrhosis ( 4 ) Undiagnosed abnormal uterine bleeding ( 4 ) Breast cancer ( 4 ) Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4 )
Warnings and precautions
Vascular risks : Stop if a thrombotic or thromboembolic event occurs. Stop at least 4 weeks before and through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breastfeeding. Consider cardiovascular risk factors before initiating in all females, particularly those over 35 years. ( 5.1 , 5.5 ) Liver disease : Discontinue if jaundice occurs. ( 5.2 ) Hypertension : If used in women with well-controlled hypertension, monitor blood pressure and stop if blood pressure rises significantly.
( 5.4 ) Gallbladder disease : May cause or worsen gallbladder disease. ( 5.5 ) Adverse carbohydrate and lipid effects : Monitor glucose in prediabetic and diabetic women taking levonorgestrel and ethinyl estradiol tablets. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. ( 5.7 ) Headache : Evaluate significant change in headaches and discontinue if indicated. ( 5.8 ) Uterine bleeding : May cause irregular bleeding or amenorrhea.
Evaluate for other causes if symptoms persist. ( 5.9 )
5.1Thromboembolic Disorders and Other Vascular Conditions
Stop levonorgestrel and ethinyl estradiol tablets if an arterial or venous thrombotic/thromboembolic event occurs. Stop levonorgestrel and ethinyl estradiol tablets if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. Discontinue levonorgestrel and ethinyl estradiol tablets during prolonged immobilization. If feasible, stop levonorgestrel and ethinyl estradiol tablets at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.
Start levonorgestrel and ethinyl estradiol tablets no earlier than 4 weeks after delivery, in females who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week. Before starting levonorgestrel and ethinyl estradiol tablets evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. levonorgestrel and ethinyl estradiol tablets is contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases [see Contraindications ( 4 )].
Arterial Events COCs increase the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke. The risk is greater among older women (> 35 years of age), smokers, and females with hypertension, dyslipidemia, diabetes, or obesity. Levonorgestrel and ethinyl estradiol tablets is contraindicated in women over 35 years of age who smoke [see Contraindications ( 4 )]. Cigarette smoking increases the risk of serious cardiovascular events from COC use.
This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. Venous Events Use of COCs increases the risk of venous thromboembolic events (VTEs), such as deep vein thrombosis and pulmonary embolism. Risk factors for VTEs include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of COCs [see Contraindications ( 4 )].
While the increased risk of VTE associated with use of COCs is well-established, the rates of VTE are even greater during pregnancy, and especially during the postpartum period (see Figure 1). The rate of VTE in females using COCs has been estimated to be 3 to 9 cases per 10,000 woman-years. The risk of VTE is highest during the first year of use of a COC and when restarting hormonal contraception after a break of four weeks or longer.
The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued. Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use oral contraceptives, for females who use oral contraceptives, for pregnant females and for females in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 females who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these females will develop a VTE.
Use of levonorgestrel and ethinyl estradiol tablets provide women with more hormonal exposure on a yearly basis than conventional monthly COCs containing the same strength synthetic estrogens and progestins (an additional 9 weeks of exposure per year). In the clinical trial, one case of pulmonary embolism was reported. Postmarketing adverse reactions of VTE have been reported in women who used levonorgestrel and ethinyl estradiol tablets.
and ethinyl estradiol tablets is contraindicated in females with acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see Contraindications ( 4 )] . Acute liver test abnormalities may necessitate the discontinuation of levonorgestrel and ethinyl estradiol tablets until the liver tests return to normal and levonorgestrel and ethinyl estradiol tablets causation has been excluded. Discontinue levonorgestrel and ethinyl estradiol tablets if jaundice develops.
Liver Tumors Levonorgestrel and ethinyl estradiol tablets are contraindicated in females with benign and malignant liver tumors [see Contraindications ( 4 )] . COCs increase the risk of hepatic adenomas. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users.
The attributable risk of liver cancers in COC users is less than one case per million users.
5.3Risk of Liver Enzyme Elevations with Concomitant Hepatitis
C treatment During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 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 levonorgestrel and ethinyl estradiol tablets.
Discontinue levonorgestrel and ethinyl estradiol tablets prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications ( 4 )]. Levonorgestrel and ethinyl estradiol tablets can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.
5.4Hypertension Levonorgestrel
and ethinyl estradiol tablets are contraindicated in females with uncontrolled hypertension or hypertension with vascular disease [see Contraindications ( 4 )] . For all women, including those with well-controlled hypertension, monitor blood pressure at routine visits and stop levonorgestrel and ethinyl estradiol tablets if blood pressure rises significantly. An increase in blood pressure has been reported in females taking COCs, and this increase is more likely in older women and with extended duration of use.
The effect of COCs on blood pressure may vary according to the progestin in the COC.
5.5Age-related Considerations
The risk for cardiovascular disease and prevalence of risk factors for cardiovascular disease increase with age. Certain conditions, such as smoking and migraine headache without aura, that do not contraindicate COC use in younger females, are contraindications to use in women over 35 years of age [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )]. Consider the presence of underlying risk factors that may increase the risk of cardiovascular disease or VTE, particularly before initiating levonorgestrel and ethinyl estradiol tablets for women over 35 years, such as: Hypertension Diabet
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Interactions
The sections below provide information on substances for which data on drug interactions with COCs are available. There is little information available about the clinical effect of most drug interactions that may affect COCs. However, based on the known pharmacokinetic effects of these drugs, clinical strategies to minimize any potential adverse effect on contraceptive effectiveness or safety are suggested. Consult the approved product labeling of all concurrently used drugs to obtain further information about interactions with COCs or the potential for metabolic enzyme or transporter system alterations.
No drug-drug interaction studies were conducted with levonorgestrel and ethinyl estradiol tablets. Enzyme inducers (e.g.CYP3A4): May decrease the effectiveness of Levonorgestrel and ethinyl estradiol tablets or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with Levonorgestrel and ethinyl estradiol tablets. ( 7.1 )
7.1Effects of Other Drugs on Combined Oral Contraceptives
Substances decreasing the plasma concentrations of COCs and potentially diminishing the efficacy of COCs: Table 5 includes substances that demonstrated an important drug interaction with levonorgestrel and ethinyl estradiol tablets. Table 5: Significant Drug Interactions Involving Substances That Affect COCs a Induction potency of St. John's wort may vary widely based on preparation. Metabolic Enzyme Inducers Clinical effect Concomitant use of COCs with metabolic enzyme inducers may decrease the plasma concentrations of the estrogen and/or progestin component of COCs.
Decreased exposure of the estrogen and/or progestin component of COCs may potentially diminish the effectiveness of COCs and may lead to contraceptive failure or an increase in breakthrough bleeding. Prevention or management Counsel females to use an alternative method of contraception or a backup method when enzyme inducers are used with COCs. Continue backup contraception for 28 days after discontinuing the enzyme inducer to maintain contraceptive reliability.
Examples Aprepitant, barbiturates, bosentan, carbamazepine, efavirenz, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, rifabutin, rufinamide, topiramate, products containing St. John's worta, and certain protease inhibitors (see separate section on protease inhibitors below). Colesevelam Clinical effect Concomitant use of COCs with colesevelam significantly decreases systemic exposure of ethinyl estradiol [see Clinical Pharmacology (12.3)].
Decreased exposure of the estrogen component of COCs may potentially reduce contraceptive efficacy or result in an increase in breakthrough bleeding, depending on the strength of ethinyl estradiol in the COC. Prevention or management Administer 4 or more hours apart to attenuate this drug interaction. Substances increasing the systemic exposure of COCs: Co-administration of atorvastatin or rosuvastatin and certain COCs containing ethinyl estradiol (EE) increase AUC values for EE by approximately 20 to 25%.
Ascorbic acid and acetaminophen may increase systemic exposure of EE possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase systemic exposure of estrogen and/or progestin component of COCs. Human immunodeficiency virus (HIV)/ Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant decreases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with some HIV protease inhibitors (e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or some HCV protease inhibitors (e.g. boceprevir and telaprevir) and some non-nucleosidase reverse transcriptase inhibitors (e.g. nevirapine).
In contrast, significant increases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with certain other HIV protease inhibitors (e.g., indinavir and atazanavir/ritonavir) and with other non-nucleoside reverse transcriptase inhibitors (e.g., etravirine).
7.2Effects of Combined Oral Contraceptives on Other Drugs Table
6 provides significant drug interaction information for drugs co-administered with levonorgestrel and ethinyl estradiol tablets. Table 6: Significant Drug Interaction Information for Drugs Co-Administered With COCs 1 volume of distribution/bioavailability. Lamotrigine Clinical effect Concomitant use of COCs with lamotrigine may significantly decrease systemic exposure of lamotrigine due to induction of lamotrigine glucuronidation [See Clinical Pharmacology (12.3)].
Decreased systemic exposure of lamotrigine may reduce seizure control. Prevention or management Dose adjustment may be necessary. Consult the approved product labeling for lamotrigine. Thyroid Hormone Replacement Therapy or Corticosteroid Replacement Therapy Clinical effect Concomitant use of COCs with thyroid hormone replacement therapy or corticosteroid replacement therapy may increase systemic exposure of thyroid-binding and cortisol-binding globulin [see Warnings and Precautions (5.12)].
Prevention or management The dose of replacement thyroid hormone or cortisol therapy may need to be increased. Consult the approved product labeling for the therapy in use [see Warnings and Precautions (5.12)]. Other Drugs Clinical effect Concomitant use of COCs may decrease systemic exposure of acetaminophen, morphine, salicylic acid, and temazepam. Concomitant use with ethinyl estradiol-containing COCs may increase systemic exposure of other drugs (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole).
Prevention or management The dosage of drugs that can be affected by this interaction may need to be increased. Consult the approved product labeling for the concomitantly used drug.
7.3Concomitant Use with Hepatitis C Vaccine (HCV) Combination
Therapy – Liver Enzyme Elevation Co-administration of levonorgestrel and ethinyl estradiol tablets with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir is contraindicated due to potential for ALT elevations [see Warning and Precautions ( 5.3 )]. Co-administration of levonorgestrel and ethinyl estradiol tablets and glecaprevir/pibrentasvir is not recommended due to potential for ALT elevations.
7.4Interactions with Laboratory Tests
The use of COCs may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
There is no use for contraception in pregnancy; therefore, levonorgestrel and ethinyl estradiol tablets should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to COCs before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 percent and 15 to 20 percent, respectively.
Adverse reactions
The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions ( 5.1 )] Vascular events [see Warnings and Precautions ( 5.1 )] Liver disease [see Warnings and Precautions ( 5.2 )] The most common adverse reactions (≥2%) reported during clinical trials were headache, menorrhagia, nausea, dysmenorrhea, acne, migraine, breast tenderness, weight increased, and depression.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The clinical trial that evaluated the safety and efficacy of levonorgestrel and ethinyl estradiol tablets was a 12-month, randomized, multicenter, open-label study, which enrolled women aged 18 to 40, of whom 456 took at least one dose of levonorgestrel and ethinyl estradiol tablets (345.14 woman-years of exposure) [see Clinical Studies ( 14 )] .
Adverse Reactions Leading to Study Discontinuation: 14.9% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions (≥ 1% of women) leading to discontinuation in the levonorgestrel and ethinyl estradiol tablets group were menorrhagia (5.7%), mood swings (1.9%), weight/appetite increase (1.5%), and acne (1.3%). Common Adverse Reactions (≥ 2% of women): headache (20.6%), menorrhagia (11.6%), nausea (7.5%), dysmenorrhea (5.7%), acne (4.6%), migraine (4.4%), breast tenderness (3.5%), weight increased (3.1%), and depression (2.1%).
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 approximately 1.4 with more than 8-10 years of COC use. Figure 2: Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives 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.
The following adverse reactions have been identified during post-approval use of levonorgestrel and ethinyl estradiol tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal disorders: abdominal distension, vomiting General disorders and administration site conditions: chest pain, fatigue, malaise, edema peripheral, pain Immune system disorder: hypersensitivity reactions, including itching, rash, and angioedema Investigations: blood pressure increased Musculoskeletal and connective tissue disorders: muscle spasms, pain in extremity Nervous system disorders: dizziness, loss of consciousness Psychiatric disorders: insomnia Reproductive and breast disorders: dysmenorrhea Skin and subcutaneous tissue disorders: alopecia Vascular disorders: thrombosis, pulmonary embolism, pulmonary thrombosis Image
Composition
Active ingredients
ETHINYL ESTRADIOL 0.03MG; LEVONORGESTREL 0.15MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
At a glance
Brand name
Levonorgestrel and Ethinyl Estradiol
Active substance
ethinyl estradiol
Drug class
Progestogens and estrogens, fixed combinations, Progestogens and estrogens, sequential preparations
