LEVONORGESTREL AND ETHINYL ESTRADIOL- levonorgestrel and ethinyl estradiol
Glenmark Pharmaceuticals Inc., USA
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HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use LEVONORGESTREL AND ETHINYL ESTRADIOL TABLETS safely and effectively. See full prescribing information for LEVONORGESTREL AND ETHINYL ESTRADIOL TABLETS.
LEVONORGESTREL and ETHINYL ESTRADIOL tablets, for oral use Initial U.S. Approval: 1982 WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTSSee full prescribing information for complete boxed warning.RECENT MAJOR CHANGESINDICATIONS AND USAGELevonorgestrel and ethinyl estradiol tablets are a combination of levonorgestrel, a progestin, and ethinyl estradiol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy. (1) DOSAGE AND ADMINISTRATIONDOSAGE FORMS AND STRENGTHSLevonorgestrel and Ethinyl Estradiol Tablets, USP consists of 84 round, light blue to blue tablets containing 0.15 mg of levonorgestrel, USP and 0.03 mg of ethinyl estradiol, USP and 7 round, white to off-white inert tablets. (3) CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
ADVERSE REACTIONSThe 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 Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONSEnzyme inducers (e.g. CYP3A4): May decrease the effectiveness of levonorgestrel and ethinyl estradiol 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. (7.1) USE IN SPECIFIC POPULATIONSSee 17 for PATIENT COUNSELING INFORMATION. Revised: 2/2023 |
Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs, including levonorgestrel and ethinyl estradiol tablets, are contraindicated in women who are over 35 years of age and smoke [see Contraindications (4) and Warnings and Precautions (5.1)].
Levonorgestrel and ethinyl estradiol tablets are indicated for use by females of reproductive potential to prevent pregnancy.
Levonorgestrel and ethinyl estradiol tablets are dispensed in an Extended-Cycle Tablet Dispenser [see How Supplied/Storage and Handling (16)]. Levonorgestrel and ethinyl estradiol tablets should be started on a Sunday (see Table 1). For the first cycle of a Sunday Start regimen, an additional method of contraception should be used until after the first 7 consecutive days of administration.
Starting levonorgestrel and ethinyl estradiol tablets in females with no current use of hormonal contraception (Sunday Start) Important: Consider the possibility of ovulation and conception prior to initiation of this product. Tablet Color:
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Sunday Start: For each 91-day course, take in the following order:
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Switching from another contraceptive method to levonorgestrel and ethinyl estradiol tablets |
Start levonorgestrel and ethinyl estradiol tablets: |
Another oral contraceptive |
On the day when the new pack of the previous COC would have been started |
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Starting Levonorgestrel and Ethinyl Estradiol Tablets after Abortion or Miscarriage
First-trimester
Second-trimester
Starting Levonorgestrel and Ethinyl Estradiol tablets after Childbirth
If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of levonorgestrel and ethinyl estradiol tablets [see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.1 and 8.2)].
Instruct patients to take one tablet by mouth at the same time every day. The dosing of levonorgestrel and ethinyl estradiol tablets is one light blue to blue pill containing levonorgestrel and ethinyl estradiol daily for 84 consecutive days, followed by one white to off-white pill (inactive pills without hormone) for 7 days. To achieve maximum contraceptive effectiveness, levonorgestrel and ethinyl estradiol tablets must be taken exactly as directed, in the order directed on the Tablet Dispenser, and at intervals not exceeding 24 hours. Start taking the first light blue to blue pill from a new Tablet Dispenser the very next day after taking the last white to off-white inactive pill in the Tablet Dispenser. The failure rate may increase when pills are missed or taken incorrectly.
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Take the tablet as soon as possible. Take the next tablet at the regular time and continue taking one tablet a day until the 91-day course is finished. |
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Take 2 tablets on the day remembered and 2 tablets the next day. Then continue taking one tablet a day until the 91-day course is finished. Additional non-hormonal contraception (such as condoms or spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets. |
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Do not take the missed tablets. Continue taking one tablet a day until the 91-day course is finished. Additional non-hormonal contraception (such as condoms or spermicide) must be used as back-up if the patient has sex within 7 days after missing tablets. |
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Throw away the missed tablets. Continue taking the remaining tablets until the pack is finished. A backup birth control method is not needed. |
In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting or diarrhea occurs within 3 to 4 hours after taking a light blue to blue tablet, handle this as a missed tablet.
Levonorgestrel and Ethinyl Estradiol Tablets, USP are available as round, biconvex, film-coated tablets debossed with 'E1' on one side and plain on the other, packaged in Extended-Cycle Tablet Dispensers, each containing a 13-week supply of tablets in the following order:
Levonorgestrel and ethinyl estradiol tablets are contraindicated in females who are known to have or develop the following conditions:
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 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.
Figure 1: Likelihood of Developing a VTE
* Pregnancy data based on actual duration of pregnancy in the reference studies. Based on a model assumption that pregnancy duration is nine months, the rate is 7 to 27 per 10,000 WY.
Use of levonorgestrel and ethinyl estradiol provides 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.
Elevated Liver Enzymes
Levonorgestrel and ethinyl estradiol 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 until the liver tests return to normal and levonorgestrel and ethinyl estradiol causation has been excluded. Discontinue levonorgestrel and ethinyl estradiol if jaundice develops.
Liver Tumors
Levonorgestrel and ethinyl estradiol is contraindicated in females with benign and malignant liver tumors [seeContraindications (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.
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. Discontinue levonorgestrel and ethinyl estradiol prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4)]. Levonorgestrel and ethinyl estradiol can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.
Levonorgestrel and ethinyl estradiol is 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 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.
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 for women over 35 years, such as:
Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs, including levonorgestrel and ethinyl estradiol, may worsen existing gallbladder disease.
A past history of COC-related cholestasis predicts an increased risk with subsequent COC use. Females with a history of pregnancy-related cholestasis may be at an increased risk for COC-related cholestasis.
Hyperglycemia
Levonorgestrel and ethinyl estradiol is contraindicated in diabetic women over age 35, or females who have diabetes with hypertension, nephropathy, retinopathy, neuropathy, other vascular disease or females with diabetes of >20 years of duration [see Contraindications (4)]. Levonorgestrel and ethinyl estradiol may decrease glucose tolerance. Carefully monitor prediabetic and diabetic females who are using levonorgestrel and ethinyl estradiol.
Dyslipidemia
Consider alternative contraception for females with uncontrolled dyslipidemia. Levonorgestrel and ethinyl estradiol may cause adverse lipid changes.
Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using levonorgestrel and ethinyl estradiol, which may increase the risk of pancreatitis.
Levonorgestrel and ethinyl estradiol is contraindicated in females who have headaches with focal neurological symptoms or have migraine headaches with aura, and in women over age 35 years who have migraine headaches with or without aura [see Contraindications (4)].
If a female taking levonorgestrel and ethinyl estradiol develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue levonorgestrel and ethinyl estradiol if indicated. Consider discontinuation of levonorgestrel and ethinyl estradiol if there is an increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) [see Contraindications (4)].
Bleeding and/or spotting that occurs at any time while taking the first 84 tablets of each extended-cycle regimen is considered "unscheduled" bleeding/spotting. Bleeding that occurs during the time a woman takes the seven white to off-white inert tablets is considered "scheduled" bleeding.
Unscheduled Bleeding and Spotting
Females using levonorgestrel and ethinyl estradiol may experience unscheduled (breakthrough or intracyclic) bleeding and spotting especially during the first 3 months of use. Bleeding irregularities may resolve over time or by changing to a different contraceptive product. If unscheduled bleeding persists or occurs after previously regular cycles, evaluate for causes such as pregnancy or malignancy.
Before prescribing levonorgestrel and ethinyl estradiol, advise the woman to weigh the occurrence of fewer scheduled menses (4 per year instead of 13 per year) against the occurrence of increased unscheduled bleeding and/or spotting.
The clinical trial of the efficacy of levonorgestrel and ethinyl estradiol (91-day cycles) in preventing pregnancy also assessed scheduled and unscheduled bleeding. The participants in the study were composed primarily of women who had used oral contraceptives previously as opposed to new users. Women with a history of breakthrough bleeding/spotting ≥ 10 consecutive days on oral contraceptives were excluded from the study. More levonorgestrel and ethinyl estradiol subjects, compared to subjects on the comparator 28-day cycle regimen, discontinued prematurely for unacceptable bleeding (7.7% [levonorgestrel and ethinyl estradiol] vs. 1.8% [28-day cycle regimen]).
Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. Table 3 below presents the number of days with unscheduled bleeding and/or spotting for each respective 91-day cycle.
Cycle (N) | Days of Unscheduled Bleeding and/or Spotting per 84-Day Interval | Median Days Per Subject-Month | |||
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Mean | Q1 | Median | Q3 | ||
1 (446) |
15.1 |
3 |
12 |
23 |
3 |
2 (368) |
11.6 |
2 |
6 |
17.5 |
1.5 |
3 (309) |
10.6 |
1 |
6 |
15 |
1.5 |
4 (282) |
8.8 |
1 |
4 |
14 |
1 |
Q1=Quartile 1: 25% of women had ≤ this number of days of unscheduled bleeding/spotting Median: 50% of women had ≤ this number of days of unscheduled bleeding/spotting
Q3=Quartile 3: 75% of women had ≤ this number of days of unscheduled bleeding/spotting
Table 4 shows the percentages of women with ≥7 days and ≥20 days of unscheduled spotting and/or bleeding in the levonorgestrel and ethinyl estradiol and the 28-day cycle treatment groups.
Days of unscheduled bleeding and/or spotting | Percentage of Subjects a | |||||||
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a Based on spotting and/or bleeding on days 1 to 84 of a 91 day cycle in the levonorgestrel and ethinyl estradiol subjects and days 1 to 21 of a 28 day cycle over 4 cycles in the 28-day dosing regimen. | ||||||||
Levonorgestrel and ethinyl estradiol |
Cycle 1 (N=385) |
Cycle 4 (N=261) |
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≥ 7 days |
65% |
42% |
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≥ 20 days |
35% |
15% |
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28-day regimen |
Cycles 1 to 4 (N=194) |
Cycles 10 to 13 (N=158) |
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≥ 7 days |
38% |
39% |
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≥ 20 days |
6% |
4% |
Total days of bleeding and/or spotting (scheduled plus unscheduled) were similar over one year of treatment for levonorgestrel and ethinyl estradiol subjects and subjects on the 28-day cycle regimen.
Amenorrhea and Oligomenorrhea
Females who use levonorgestrel and ethinyl estradiol may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant. Based on data from the clinical trial of levonorgestrel and ethinyl estradiol, amenorrhea occurred in approximately 0.8% of females during Cycle 1, 1.2% of females during Cycle 2, 3.7% of females during Cycle 3, and 3.4% of females during Cycle 4.
Because females using levonorgestrel and ethinyl estradiol will likely have scheduled bleeding only 4 times per year, rule out pregnancy at the time of any missed menstrual period.
After discontinuation of levonorgestrel and ethinyl estradiol, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent.
Carefully observe females with a history of depression and discontinue levonorgestrel and ethinyl estradiol if depression recurs to a serious degree. Data on the association of COCs with onset of depression or exacerbation of existing depression are limited.
Breast Cancer
Levonorgestrel and ethinyl estradiol is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4)].
Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use [see Postmarketing Experience (6.2)].
Cervical Cancer
Some studies suggest that COC are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.
The estrogen component of levonorgestrel and ethinyl estradiol may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased.
The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling:
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 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 (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 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%).
Serious Adverse Reactions: pulmonary embolus, cholecystitis.
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 to 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 to 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 to 10 years of COC 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.
The following adverse reactions have been identified during post-approval use of levonorgestrel and ethinyl estradiol. 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
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.
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
Metabolic Enzyme Inducers |
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Clinical effect |
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Prevention or management |
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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 |
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Clinical effect |
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Prevention or management |
Administer 4 or more hours apart to attenuate this drug interaction. |
a Induction potency of St. John’s wort may vary widely based on preparation.
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 20-25%. 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).
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
Lamotrigine |
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Clinical effect |
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Prevention or management |
Dose adjustment may be necessary. Consult the approved product labeling for lamotrigine. |
Thyroid Hormone Replacement Therapy or Corticosteroid Replacement Therapy |
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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 |
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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. |
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.
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.
Risk Summary
Contraceptive hormones and/or metabolites are present in human milk. COCs can reduce milk production in breastfeeding females. This reduction can occur at any time but is less likely to occur once breastfeeding is well-established. When possible, advise the nursing female to use other methods of contraception until she discontinues breastfeeding [see Dosage and Administration (2.1)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for levonorgestrel and ethinyl estradiol tablets and any potential adverse effects on the breastfed child from levonorgestrel and ethinyl estradiol tablets or the underlying maternal condition.
Safety and efficacy of levonorgestrel and ethinyl estradiol have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 as for users 18 years and older. Use of levonorgestrel and ethinyl estradiol before menarche is not indicated.
Levonorgestrel and ethinyl estradiol has not been studied in postmenopausal women and is not indicated in this population.
The pharmacokinetics of levonorgestrel and ethinyl estradiol have not been studied in subjects with hepatic impairment. However, COCs may be poorly metabolized in patients with hepatic impairment. Levonorgestrel and ethinyl estradiol tablets are contraindicated in females with acute hepatitis or severe decompensated cirrhosis [see Contraindications (4) and Warnings and Precautions (5.2)].
There have been no reports of serious ill effects from overdose of oral contraceptives, including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea.
Levonorgestrel and Ethinyl Estradiol Tablets, USP are an extended-cycle combination oral contraceptive consisting of 84 light blue to blue active tablets each containing 0.15 mg of levonorgestrel, USP, a synthetic progestin and 0.03 mg of ethinyl estradiol, USP, an estrogen, and 7 white to off-white inert tablets (without hormones).
The structural formulas for the active components are:
Levonorgestrel, USP
C21H28O2 MW: 312.45
Levonorgestrel, USP is chemically 18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-, (17α)-, (-)-.
Ethinyl Estradiol, USP
C20H24O2 MW: 296.4
Ethinyl Estradiol, USP is 19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-.
No specific pharmacodynamic studies were conducted with levonorgestrel and ethinyl estradiol.
Absorption
No specific investigation of the absolute bioavailability of levonorgestrel and ethinyl estradiol in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability nearly 100%) and is not subject to first-pass metabolism. EE is rapidly and almost completely absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, the bioavailability of EE is approximately 43%.
Following continuous dosing with once-daily administration of levonorgestrel and ethinyl estradiol tablets, plasma concentrations of levonorgestrel and EE reached steady-state within 7 days. The mean plasma pharmacokinetic parameters for levonorgestrel and ethinyl estradiol under fasting conditions in normal healthy women following once-daily administration of one levonorgestrel/EE combination tablet for 10 days are summarized in Table 7.
a Cavg = AUC0 to 24/24 | |||||
Analyte
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AUC0 to 24
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Cmax
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Cmin
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Cavga
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Tmax
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Levonorgestrel |
54.6 ± 16.5 |
5 ± 1.5 ng/mL |
1.6 ± 0.5 |
2.3 ± 0.7 ng/mL |
1.4 ± 0.7 hours |
Ethinyl estradiol |
935.5 ± 346.9 |
106.1 ± 41.2 |
18.5 ± 9.4 pg/mL |
38.9 ± 14.4 pg/mL |
1.6 ± 0.6 |
Food Effect
The effect of food on the rate and the extent of levonorgestrel and EE absorption following oral administration of levonorgestrel and ethinyl estradiol has not been evaluated.
Distribution
The apparent volume of distribution of levonorgestrel and EE are reported to be approximately 1.8 L/kg and 4.3 L/kg, respectively. Levonorgestrel is about 97.5 to 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin. EE is about 95 to 97% bound to serum albumin. EE does not bind to SHBG, but induces SHBG synthesis, which leads to decreased levonorgestrel clearance. Following repeated daily dosing of levonorgestrel/EE oral contraceptives, levonorgestrel plasma concentrations accumulate more than predicted based on single-dose pharmacokinetics, due in part, to increased SHBG levels that are induced by EE, and a possible reduction in hepatic metabolic capacity.
Metabolism
Following absorption, levonorgestrel is conjugated at the 17β-OH position to form sulfate and to a lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3α,5β-tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3α,5α-tetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. Levonorgestrel and its phase I metabolites are excreted primarily as glucuronide conjugates. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users.
First-pass metabolism of EE involves formation of EE-3-sulfate in the gut wall, followed by 2-hydroxylation of a portion of the remaining untransformed EE by hepatic cytochrome P-450 3A4 (CYP3A4). Levels of CYP3A4 vary widely among individuals and can explain the variation in rates of EE hydroxylation. Hydroxylation at the 4-, 6-, and 16-positions may also occur, although to a much lesser extent than 2-hydroxylation. The various hydroxylated metabolites are subject to further methylation and/or conjugation.
Excretion
About 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. The terminal elimination half-life for levonorgestrel after a single dose of levonorgestrel and ethinyl estradiol was about 30 hours.
EE is excreted in the urine and feces as glucuronide and sulfate conjugates, and it undergoes enterohepatic recirculation. The terminal elimination half-life of EE after a single dose of levonorgestrel and ethinyl estradiol was found to be about 15 hours.
In a 12-month, multicenter, randomized, open-label clinical trial, 456 women aged 18 to 40 were studied to assess the safety and efficacy of levonorgestrel and ethinyl estradiol, completing 809 91-day cycles of exposure. The racial demographic of those enrolled was: Caucasian (77%), African-American (11%), Hispanic (7%), Asian (2%), and Other (3%).
There were no exclusions for body mass index (BMI) or weight. The weight range of those women treated was 84 to 304 pounds, with a mean weight of 157 pounds and a median weight of 147 pounds. Among the women in the trial, 63% were current or recent hormonal contraceptive users, 29% were prior users (who had used hormonal contraceptives in the past but not in the 6 months prior to enrollment), and 8% were new starts.
The pregnancy rate (Pearl Index [PI]) in the 397 women aged 18 to 35 years was 1.98 pregnancies per 100 women-years of use (95% CI: 0.54 to 5.03), based on 4 pregnancies that occurred after the onset of treatment and within 14 days after the last combination pill. Cycles in which conception did not occur, but which included the use of back-up contraception, were not included in the calculation of the PI.
How Supplied
Levonorgestrel and Ethinyl Estradiol Tablets, USP 0.15 mg/0.03 mg are available in Extended-Cycle Tablet Dispensers, each containing a 13-week supply of tablets:
NDC 68462-672-95 – 1 carton containing 3 foil pouches. Inside each pouch is 1 Extended-Cycle Tablet Dispenser containing 84 light blue to blue tablets and 7 white to off-white tablets.
Storage and Handling
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Cigarette Smoking
Cigarette smoking increases the risk of serious cardiovascular events from COC use. Women who are over 35 years old and smoke should not use levonorgestrel and ethinyl estradiol tablets [see Boxed Warning and Warnings and Precautions (5.1)].
Venous Thromboembolism
The increased risk of VTE compared to non-users of COCs is greatest after initially starting a COC or restarting (following a 4-week or greater pill-free interval) the same or a different COC [see Warnings and Precautions (5.1)].
Use During Pregnancy
Instruct females to stop further intake of levonorgestrel and ethinyl estradiol tablets if pregnancy is confirmed during treatment.
Sexually Transmitted Infections
Levonorgestrel and ethinyl estradiol tablets does not protect against HIV-infection (AIDS) and other sexually transmitted infections.
Dosing and Missed Pill Instructions
Need for Additional Contraception
Lactation
Levonorgestrel and ethinyl estradiol tablets may reduce breast milk production. This is less likely to occur if breastfeeding is well established. When possible, nursing women should use other methods of contraception until they have discontinued breastfeeding [see Use in Specific Populations (8.2)].
Amenorrhea and Possible Symptoms of Pregnancy
Amenorrhea may occur. Because women using levonorgestrel and ethinyl estradiol tablets will likely have scheduled bleeding only 4 times per year, advise women to contact their health care provider in the event of amenorrhea with symptoms of pregnancy such as morning sickness or unusual breast tenderness [see Warnings and Precautions (5.9)].
Depression
Depressed mood and depression may occur. Women should contact their healthcare provider if mood changes and depressive symptoms occur, including shortly after initiating the treatment [see Warnings and Precautions (5.10)].
Manufactured by:
Glenmark Pharmaceuticals Limited
Colvale-Bardez, Goa 403513, India
Manufactured for:
Glenmark Pharmaceuticals Inc., USA
Mahwah, NJ 07430
Questions? 1 (888) 721-7115
www.glenmarkpharma-us.com
February 2023
FDA-approved Patient Labeling
Patient Information
Levonorgestrel and Ethinyl Estradiol (LEE-voe-nor-JES-trel and ETH-i-nil ES-tra-DYE-ol)
Tablets, USP
WARNING TO WOMEN WHO SMOKE Do not use levonorgestrel and ethinyl estradiol tablets if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects from birth control pills, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke. |
What is the most important information I should know about levonorgestrel and ethinyl estradiol tablets?
Do not use levonorgestrel and ethinyl estradiol tablets if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects from birth control pills, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke.
What is levonorgestrel and ethinyl estradiol tablets?
Levonorgestrel and ethinyl estradiol tablet is a birth control pill (oral contraceptive) used by women to prevent pregnancy. It contains two female hormones, an estrogen called ethinyl estradiol, and a progestin called levonorgestrel. Levonorgestrel and ethinyl estradiol tablets does not protect against HIV infections (AIDS) and other sexually transmitted infections.
How does levonorgestrel and ethinyl estradiol tablets work for contraception?
Your chance of getting pregnant depends on how well you follow the directions for taking your birth control pills. The better you follow the directions, the less chance you have of getting pregnant.
Based on the results of clinical studies, about 1 to 5 out of 100 women may get pregnant during the first year they use levonorgestrel and ethinyl estradiol tablets.
The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant.
Who should not take levonorgestrel and ethinyl estradiol tablets?
Do not take levonorgestrel and ethinyl estradiol tablets if you:
If any of these conditions happen to you while you are taking levonorgestrel and ethinyl estradiol tablets, stop taking levonorgestrel and ethinyl estradioltablets right away and talk to your healthcare provider. Use non-hormonal contraception when you stop taking levonorgestrel and ethinyl estradioltablets.
What should I tell my healthcare provider before taking levonorgestrel and ethinyl estradiol tablets?
Tell your healthcare provider if you:
Tell your healthcare provider if you have ever had any of the conditions listed in, “Who should not take levonorgestrel and ethinyl estradiol tablets” above. Your healthcare provider may recommend another method of birth control.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.
Levonorgestrel and ethinyl estradiol tablets may affect the way other medicines work, and other medicines may affect how well levonorgestrel and ethinyl estradiol tablets works.
Some medicines and herbal products may make birth control pills less effective, including:
Use a back-up or alternative birth control method when you take medicines that may make birth control pills less effective.
Birth control pills may interact with lamotrigine, an anticonvulsant used for epilepsy. This may increase the risk of seizures, so your physician may need to adjust the dose of lamotrigine.
Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take levonorgestrel and ethinyl estradiol tablets?
Read the Instructions for Use at the end of this Patient Information.
What are the most serious risks of taking levonorgestrel and ethinyl estradiol tablets?
Like pregnancy, levonorgestrel and ethinyl estradiol tablets may cause serious side effects, including blood clots in your lungs, heart attack, or a stroke that may lead to death. Some other examples of serious blood clots include blood clots in the legs or eyes. Serious blood clots can happen especially if you smoke, are obese, or are older than 35 years of age. Serious blood clots are more likely to happen when you:
Call your healthcare provider or go to a hospital emergency room right away if you have:
Other serious side effects include:
What are the most common side effects of levonorgestrel and ethinyl estradiol tablets?
These are not all the possible side effects of levonorgestrel and ethinyl estradiol tablets. For more information, ask your healthcare provider or pharmacist.
You may report side effects to the FDA at 1-800-FDA-1088.
What else should I know about taking levonorgestrel and ethinyl estradioltablets?
How should I store levonorgestrel and ethinyl estradioltablets?
General information about the safe and effective use of levonorgestrel and ethinyl estradiol tablets.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use levonorgestrel and ethinyl estradiol tablets for a condition for which they were not prescribed. Do not give levonorgestrel and ethinyl estradiol tablets to other people, even if they have the same symptoms that you have.
This Patient Information summarizes the most important information about levonorgestrel and ethinyl estradiol tablets. You can ask your pharmacist or healthcare provider for information about levonorgestrel and ethinyl estradiol tablets that is written for health professionals.
For more information, call 1 (888) 721-7115.
Do birth control pills cause cancer?
It is not known if hormonal birth control pills cause breast cancer. Some studies, but not all, suggest that there could be a slight increase in the risk of breast cancer among current users with longer duration of use.
If you have breast cancer now, or have had it in the past, do not use hormonal birth control because some breast cancers are sensitive to hormones. Women who use birth control pills may have a slightly higher chance of getting cervical cancer. However, this may be due to other reasons such as having more sexual partners.
What if I want to become pregnant?
You may stop taking the pill whenever you wish. Consider a visit with your healthcare provider for a pre-pregnancy checkup before you stop taking the pill.
What should I know about my period when taking levonorgestrel and ethinyl estradioltablets?
When you take levonorgestrel and ethinyl estradiol tablets, which has a 91-day extended dosing cycle, you should have 4 scheduled periods a year (bleeding when you are taking the 7 white to off-white pills). However, you will probably have more bleeding or spotting between your scheduled periods than if you were using a birth control pill with a 28-day dosing cycle. During the first levonorgestrel and ethinyl estradiol tablets 91-day treatment cycle, about 1 in 3 women may have 20 or more days of unplanned bleeding or spotting. This bleeding or spotting tends to decrease with time. Do not stop taking levonorgestrel and ethinyl estradiol tablets because of this bleeding or spotting. If the spotting continues for more than 7 days in a row or if the bleeding is heavy, call your healthcare provider.
What if I miss my scheduled period when taking levonorgestrel and ethinyl estradiol tablets?
You should consider the possibility that you are pregnant if you miss your scheduled period (no bleeding on the days that you are taking white to off-white pills). Since scheduled periods are less frequent when you are taking levonorgestrel and ethinyl estradiol tablets, notify your healthcare provider that you have missed your period and that you are taking levonorgestrel and ethinyl estradiol tablets. Also notify your healthcare provider if you have symptoms of pregnancy such as morning sickness or unusual breast tenderness. It is important that your healthcare provider evaluates you to determine if you are pregnant. Stop taking levonorgestrel and ethinyl estradiol tablets if it is determined that you are pregnant.
What are the ingredients in levonorgestrel and ethinyl estradiol tablets?
Active ingredients: Each light blue to blue active tablet contains levonorgestrel, USP and ethinyl estradiol, USP.
Inactive ingredients:
Each light blue to blue active tablet contains the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, hypromellose, anhydrous lactose, talc, magnesium stearate, titanium dioxide, triacetin, FD&C blue no. 1 aluminum lake, FD&C yellow no. 6 aluminum lake, D&C yellow no. 10 aluminum lake.
Each white to off-white inert tablet contains the following inactive ingredients: lactose monohydrate, anhydrous lactose, microcrystalline cellulose, hypromellose, polacrilin potassium, magnesium stearate.
Manufactured by:
Glenmark Pharmaceuticals Limited
Colvale-Bardez, Goa 403513, India
Manufactured for:
Glenmark Pharmaceuticals Inc., USA
Mahwah, NJ 07430
Questions? 1 (888) 721-7115
www.glenmarkpharma-us.com
February 2023
Levonorgestrel and Ethinyl Estradiol (LEE-voe-nor-JES-trel and aETH-i-nil ES-tra-DYE-ol)
Tablets, USP
Important Information about taking levonorgestrel and ethinyl estradiol tablets
Before you start taking levonorgestrel and ethinyl estradiol tablets:
Figure A
Figure B
When should I start taking levonorgestrel and ethinyl estradiol tablets?
If you start taking levonorgestrel and ethinyl estradiol tablets and you have not used a hormonal birth control method before:
If you have recently given birth and have not yet had a period, use another method of birth control if you have sex (such as condoms and spermicides) as a back-up method until you have taken LOSEASONIQUE for 7 days.
If you start taking levonorgestrel and ethinyl estradiol tablets and you are switching from another birth control pill:
If you start taking levonorgestrel and ethinyl estradiol tablets and previously used a vaginal ring:
If you start taking levonorgestrel and ethinyl estradiol tablets and previously used a transdermal patch:
If you start taking levonorgestrel and ethinyl estradiol tablets and you are switching from a progestin-only method such as an implant or injection:
If you start taking levonorgestrel and ethinyl estradiol tablets and you are switching from an intrauterine device or system (IUD or IUS):
Keep a calendar to track your period: If this is the first time you are taking birth control pills, read, "When should I start taking levonorgestrel and ethinyl estradioltablets?" above. Follow these instructions for a Sunday Start.
Instructions for using your levonorgestrel and ethinyl estradiol Extended-Cycle Tablet Dispenser:
Sunday Start:
Figure C
What should I do if I miss any levonorgestrel and ethinyl estradiol tablets?
If you miss 1 light blue to blue pill, follow these steps:
If you miss 2 light blue to blue pills in a row, follow these steps:
If you miss 3 or more light blue to blue pills in a row, follow these steps:
If you miss any of the 7 white to off-white pills:
Finally, if you are still not sure what to do about the pills you have missed
If you have any questions or are unsure about the information in this leaflet, call your healthcare provider.
Manufactured by:
Glenmark Pharmaceuticals Limited
Colvale-Bardez, Goa 403513, India
Manufactured for:
Glenmark Pharmaceuticals Inc., USA
Mahwah, NJ 07430
Questions? 1 (888) 721-7115
www.glenmarkpharma-us.com
This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.
February 2023
LEVONORGESTREL AND ETHINYL ESTRADIOL
levonorgestrel and ethinyl estradiol kit |
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Labeler - Glenmark Pharmaceuticals Inc., USA (130597813) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
---|---|---|---|
Glenmark Pharmaceuticals Limited | 677318665 | ANALYSIS(68462-672) , MANUFACTURE(68462-672) |