TYBLUME- levonorgestrel and ethinyl estradiol
Exeltis USA, Inc.
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use TYBLUME safely and effectively. See full prescribing information for TYBLUME.
TYBLUME (levonorgestrel and ethinyl estradiol) tablets, for oral use
Initial U.S. Approval: 1968 (norgestrel and ethinyl estradiol)
WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS
See full prescribing information for complete boxed warning.
INDICATIONS AND USAGE
TYBLUME (levonorgestrel and ethinyl estradiol tablets) is 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 ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
A TYBLUME pack consists of 28 tablets: (3)
WARNINGS AND PRECAUTIONS
Common adverse reactions are: headache, abdominal pain, nausea, metrorrhagia, vaginal moniliasis and pain, acne, and vaginitis. ( 6)
To report SUSPECTED ADVERSE REACTIONS, contact Exeltis USA, Inc. at 1-877-324-9349 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Enzyme inducers (e.g., CYP3A4): May decrease the effectiveness of TYBLUME or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with TYBLUME. ( 7.1, 7.2)
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Important Administration Instructions
2.2 Additional Administration Information
2.3 Missed Doses
2.4 Administration Recommendations after Vomiting or Acute Diarrhea
3 DOSAGE FORMS AND STRENGTHS
5 WARNINGS AND PRECAUTIONS
5.1 Thromboembolic Disorders and Other Vascular Problems
5.2 Liver Disease
5.4 Age-related Considerations
5.5 Gallbladder Disease
5.6 Adverse Carbohydrate and Lipid Metabolic Effects
5.8 Bleeding Irregularities and Amenorrhea
5.10 Cervical Cancer
5.11 Effect on Binding Globulins
5.12 Hereditary Angioedema
5.14 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment
6 ADVERSE REACTIONS
7 DRUG INTERACTIONS
7.1 Effects of Other Drugs on Combined Hormonal Contraceptives
7.2 Effects of Combined Hormonal Contraceptives on Other Drugs
7.3 Effect on Laboratory Tests
7.4 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation
8 USE IN SPECIFIC POPULATIONS
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
8.7 Body Mass Indexes
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Storage and Handling
17 PATIENT COUNSELING INFORMATION
Cigarette smoking increases the risk of serious cardiovascular events from combined hormonal contraceptive (CHC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, CHCs, including TYBLUME (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)].
TYBLUME is indicated for use by females of reproductive potential to prevent pregnancy.
Take TYBLUME in one of two ways: (1) swallow whole on an empty stomach or (2) chew and then immediately swallow with a full glass of 240 mL of water on an empty stomach [see Dosage and Administration (2.2)].
To achieve maximum contraceptive effectiveness, take TYBLUME exactly as directed (one tablet orally at the same time every day) and at intervals not exceeding 24 hours. The failure rate may increase when tablets are missed or taken incorrectly. The recommended dosage of TYBLUME is one tablet daily for 28 consecutive days: one white active tablet daily during the first 21 consecutive days, followed by one peach inactive tablet daily during the 7 following days (see Table 1).
|Starting TYBLUME in females with no current use of hormonal contraception (start on Day 1 or Sunday)|
|Day 1 start
|Switching to TYBLUME from another contraceptive method|
|Complete instructions to facilitate patient counseling on proper tablet usage are located in the FDA-Approved Patient Labeling (Instructions for Use).|
Instruct patients about the handling of missed doses (e.g., to take a missed tablet as soon as possible) and to follow the dosing instructions provided in the FDA-approved patient labeling (Instructions for Use).
||Take the missed active tablet as soon as possible, even if two active tablets are taken in one day. Continue taking one tablet a day until the pack is finished.|
||Take two active tablets as soon as possible. Then, take two active tablets the next day. This means taking 4 tablets in 2 days. Continue taking one tablet a day until the pack is finished. Additional nonhormonal contraception (such as condoms and spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets.|
||Day 1 start: Throw out the rest of the 28-day pack and start a new pack that same day.
Sunday start: Continue taking one tablet a day until Sunday, then throw out the rest of the pack and start a new pack that same day. Additional nonhormonal contraception (such as condoms and spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets.
||Throw away the missed inactive tablets. Keep taking one tablet each day until the pack is empty. Back-up nonhormonal birth-control method is not needed but take the next pack on time.|
If vomiting or acute diarrhea occurs within 3 to 4 hours after taking an active tablet, take the new active tablet (scheduled for the next day) as soon as possible. If more than two active tablets are missed, see the recommendations in Table 2 [see Dosage and Administration (2.3)].
One pack of TYBLUME consists of 28 tablets:
TYBLUME is contraindicated in females who are known to have the following conditions:
Before starting TYBLUME evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. TYBLUME is contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases [see Contraindications (4)].
CHCs 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.
TYBLUME is contraindicated in women over 35 years of age who smoke [see Contraindications (4)] . Cigarette smoking increases the risk of serious cardiovascular events from CHC use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked.
Use of CHCs 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 CHCs [see Contraindications (4)] . While the increased risk of VTE associated with use of CHCs 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 CHC and when restarting hormonal contraception after a break of four weeks or longer. Based on results from a few studies, there is some evidence that this is true for non-oral products as well. The risk of thromboembolic disease due to CHCs gradually disappears after CHC 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.
|*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.|
|Figure 1 Likelihood of Developing a VTE|
Elevated Liver Enzymes
TYBLUME is contraindicated in females with acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see Contraindications (4)]. Discontinue TYBLUME if jaundice develops. Acute liver test abnormalities may necessitate the discontinuation of CHC use until the liver tests return to normal and CHC causation has been excluded.
TYBLUME is contraindicated in females with benign or malignant liver tumors [see Contraindications (4)] . CHCs increase the risk of hepatic adenomas. An estimate of the attributable risk is 3.3 cases/100,000 CHC users. Rupture of hepatic adenomas may cause death from abdominal hemorrhage.
Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) CHC users. The attributable risk of liver cancers in CHC users is less than one case per million users.
TYBLUME is contraindicated in females with uncontrolled hypertension or hypertension with vascular disease [see Contraindications (4)] . For all females, including those with well-controlled hypertension, monitor blood pressure at routine visits and stop TYBLUME if blood pressure rises significantly.
An increase in blood pressure has been reported in females using CHCs, and this increase is more likely in older women with extended duration of use. The effect of CHCs on blood pressure may vary according to the progestin in the CHC.
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 CHC 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 a CHC for women over 35 years, such as:
Studies suggest an increased risk of developing gallbladder disease among CHC users. Use of CHCs may also worsen existing gallbladder disease.
A past history of CHC-related cholestasis predicts an increased risk with subsequent CHC use. Females with a history of pregnancy-related cholestasis may be at an increased risk for CHC related cholestasis.
TYBLUME 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 duration [see Contraindications (4)]. TYBLUME may decrease glucose tolerance. Carefully monitor prediabetic and diabetic females who are using TYBLUME.
Consider alternative contraception for females with uncontrolled dyslipidemia. TYBLUME may cause adverse lipid changes.
Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using TYBLUME, which may increase the risk of pancreatitis.
TYBLUME 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 woman using TYBLUME develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue TYBLUME if indicated. Consider discontinuation of TYBLUME if there is an increased frequency or severity of migraines during CHC use (which may be prodromal of a cerebrovascular event).
Unscheduled Bleeding and Spotting
Females using TYBLUME may experience unscheduled (breakthrough or intracyclic) bleeding and spotting, especially during the first three months of use. Bleeding irregularities may resolve over time or by changing to a different contraceptive product. If bleeding persists or occurs after previously regular cycles, evaluate for causes such as pregnancy or malignancy.
Amenorrhea and Oligomenorrhea
Females who use TYBLUME may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant.
If scheduled bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or two active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and perform appropriate diagnostic measures. If the patient has adhered to the prescribed dosing schedule and misses two consecutive periods, rule out pregnancy.
After discontinuation of a CHC, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent.
Carefully observe females with a history of depression and discontinue TYBLUME if depression recurs to a serious degree. Data on the association of CHCs with onset of depression or exacerbation of existing depression are limited.
Some studies suggest that CHCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. There is controversy about the extent to which these findings are due to differences in sexual behavior and other factors.
The estrogen component of TYBLUME 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.
In females with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.
Chloasma may occur with TYBLUME use, especially in females with a history of chloasma gravidarum. Advise females with a history of chloasma to avoid exposure to the sun or ultraviolet radiation while using TYBLUME.
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 COCs. COCs are contraindicated for use with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4)] . Discontinue TYBLUME prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir.
TYBLUME can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.
The following serious adverse reactions with the use of CHCs are discussed elsewhere in labeling:
The following adverse reactions associated with the use of oral CHCs were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Common adverse reactions associated with oral CHCs are headache, abdominal pain, nausea, metrorrhagia, vaginal moniliasis and pain, acne, and vaginitis.
Additional adverse reactions that have been reported include the following:
Eye disorder: intolerance to contact lenses, steepening of corneal curvature
Gastrointestinal disorders: Abdominal bloating, vomiting
General disorders and administration site condition: Edema, fluid retention
Hepatobiliary disorders: Cholestatic jaundice
Psychiatric disorders: Change in libido, mood changes
Reproductive system and breast disorders: Amenorrhea, breast tenderness, breast pain, breast enlargement, increased cervical mucous, change in menstrual flow, unscheduled bleeding
Skin and subcutaneous tissue disorders: Acne, melasma [see Warnings and Precautions (5.13)]
Vascular disorders: Budd-Chiari syndrome, aggravation of varicose veins
The sections below provide information on substances for which data on drug interactions with CHCs are available. There is little information available about the clinical effect of most drug interactions that may affect CHCs. 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 CHCs or the potential for metabolic enzyme or transporter system alterations.
No drug-drug interaction studies were conducted with TYBLUME.
Substances decreasing the Plasma Concentration of CHCs and Potentially Diminishing the Efficacy of CHCs
|a Induction potency of St. John's wort may vary widely based on preparation.|
|Metabolic Enzyme Inducers|
|Prevention or management||
|Examples||Aprepitant, barbiturates, bosentan, carbamazepine, efavirenz, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, primidone, phenylbutazone, rifabutin, rufinamide, topiramate, products containing St. John's wort, and certain protease inhibitors (see separate section on protease inhibitors below).|
|Prevention or management||Administer 4 or more hours apart to attenuate this drug interaction.|
Substances increasing the systemic exposure of CHCs:
Co-administration of atorvastatin or rosuvastatin and CHCs containing ethinyl estradiol increase systemic exposure of ethinyl estradiol by approximately 20 to 25 percent. Ascorbic acid and acetaminophen may increase systemic exposure of ethinyl estradiol, possibly by inhibition of conjugation. CYP3A inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice 1, or ketoconazole may increase systemic exposure of the estrogen and/or progestin component of CHCs.
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 CHCs are co-administered with some HIV protease inhibitors (e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir), some HCV protease inhibitors (e.g., boceprevir and telaprevir), and some non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine).
In contrast, significant increases in systemic exposure of the estrogen and/or progestin have been noted when CHCs 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 4 provides significant drug interaction information for drugs co-administered with TYBLUME.
|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 CHCs with thyroid hormone replacement therapy or corticosteroid replacement therapy may increase systemic exposure of thyroid-binding and cortisol-binding globulin [see Warnings and Precautions (5.11)].|
|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 (5.11)].|
|Clinical effect||Concomitant use of CHCs may decrease systemic exposure of acetaminophen, morphine, salicylic acid, and temazepam. Concomitant use with ethinyl estradiol-containing CHCs 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.|
The use of CHCs may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.
CHCs are contraindicated for use with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4)]. Discontinue TYBLUME prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. TYBLUME can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.
There is no use for contraception in pregnancy; therefore, TYBLUME should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to CHCs 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.
Contraceptive hormones and/or metabolites are present in human milk. CHCs can reduce milk production in breast-feeding females. This reduction can occur at any time but is less likely to occur once breast-feeding is well established. When possible, advise the nursing female to use other methods of contraception until she discontinues breast-feeding [see Dosage and Administration (2.2)]. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for TYBLUME and any potential adverse effects on the breast-fed child from TYBLUME or from the underlying maternal condition.
Small amounts of oral-contraceptive steroids and/or metabolites have been identified in the milk of nursing mothers, and a 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.
The safety and effectiveness of TYBLUME have been established in females of reproductive potential. Efficacy is expected to be the same for post-menarchal females under the age of 17 as for users 17 years and older. The use of TYBLUME before menarche is not indicated.
TYBLUME has not been studied in postmenopausal women and is not indicated in this population.
The pharmacokinetics of TYBLUME have not been studied in women with hepatic impairment. However, steroid hormones may be poorly metabolized in patients with hepatic impairment. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded [see Contraindications (4) and Warnings and Precautions (5.2)] .
TYBLUME (levonorgestrel and ethinyl estradiol) tablets is an oral contraceptive product. A TYBLUME pack consists of 21 white active tablets and 7 peach-colored inactive tablets.
The twenty-one white active tablets each contain 0.1 mg of levonorgestrel, a progestin, and 0.02 mg of ethinyl estradiol, an estrogen. Each tablet also contains the following inactive ingredients: corn starch, crospovidone, lactose monohydrate, magnesium stearate, povidone, and pregelatinized starch.
Seven peach-colored inactive tablets, each contains anhydrous lactose, corn starch, crospovidone, D&C yellow No. 10 aluminum lake, FD&C Red No. 40 aluminum lake, magnesium stearate, and povidone.
The chemical name for levonorgestrel is [18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-, (17α)-(-)-]. It has the molecular formula of C 21H 28O 2, the molecular weight of 312.5, and the structural formula is provided below:
The chemical name for ethinyl estradiol is [19-norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-]. It has the molecular formula of C 20H 24O 2, the molecular weight of 296.4, and the structural formula is provided below:
CHCs lower the risk of becoming pregnant primarily by suppressing ovulation.
No specific investigation of the absolute bioavailability of TYBLUME 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%.
The kinetics of total levonorgestrel are non-linear due to an increase in binding of levonorgestrel to sex hormone binding globulin (SHBG), which is attributed to increased SHBG levels that are induced by the daily administration of ethinyl estradiol.
Table 5 provides a summary of pharmacokinetics of levonorgestrel and ethinyl estradiol after a single dose of TYBLUME in 32 female subjects only under fasting condition.
|EE||n = 32||53.22 (33.9)||1.50 (1.00-2.25)||477.75 (32.5)||515.51 (31.0)||16.42 (25.0)|
|LNG||n = 32 †||3225.0 (33.1)||0.75 (0.50-1.00)||27586.0 (39.0)||34099.0 (36.8)||33.67 (31.8)|
Levonorgestrel in serum is primarily bound to SHBG. Ethinyl estradiol is about 97% bound to plasma albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis.
Levonorgestrel: The most important metabolic pathway occurs in the reduction of the Δ4-3-oxo group and hydroxylation at positions 2α, 1β, and 16β, followed by conjugation. Most of the metabolites that circulate in the blood are sulfates of 3α,5β-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent levonorgestrel also circulates as 17β-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 and glucuronidation prior to urinary and fecal excretion. Levels of Cytochrome P450 (CYP3A) vary widely among individuals and can explain the variation in rates of ethinyl estradiol 2-hydroxylation. Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates, and undergoes enterohepatic circulation.
The elimination half-life for levonorgestrel is approximately 36 ± 13 hours at steady state. Levonorgestrel and its metabolites are primarily excreted in the urine (40% to 68%) and about 16% to 48% are excreted in feces. The elimination half-life of ethinyl estradiol is 18 ± 4.7 hours at steady state.
In a clinical trial with TYBLUME (levonorgestrel and ethinyl estradiol) tablets (0.1 mg and 0.02 mg, respectively), 1,477 subjects had 7,720 cycles of use and a total of 5 pregnancies were reported. This represented an overall pregnancy rate of 0.84 per 100 woman-years. These data included patients who did not take TYBLUME correctly. One or more tablets were missed during 1,479 (19%) of the 7,870 cycles; thus all tablets were taken during 6,391 (81%) of the 7,870 cycles. Of the total 7,870 cycles, a total of 150 cycles were excluded from the calculation of the Pearl Index due to the use of backup contraception and/or missing 3 or more consecutive tablets.
TYBLUME is available as follows:
Each blister card contains 28 tablets in the following order: 21 active tablets and 7 inactive tablets. The 21 active tablets are white, round, and debossed with 30 on one side and L2 on the other side; each contains levonorgestrel 0.1 mg and ethinyl estradiol 0.02 mg. The 7 inactive tablets (placebo) are peach-colored, round, and debossed with 1 on one side and L2 on the other
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Advise women that cigarette smoking increases the risk of serious cardiovascular events from CHC use, and that women who are over 35 years old and smoke should not use TYBLUME [see Boxed Warning and Warning and Precautions (5.1)] .
Advise women that the increased risk of VTE compared to non-users of CHCs is greatest after initially starting a CHC or restarting (following a 4-week or greater tablet-free interval) the same or a different CHC [see Warnings and Precautions (5.1)] .
Use During Pregnancy
Advise women that there is no reason to use TYBLUME during pregnancy. Instruct the woman to stop TYBLUME if pregnancy is confirmed during treatment [see Use in Specific Populations (8.1)].
Sexually Transmitted Infections
Advise women that TYBLUME does not protect against HIV-infection (AIDS) and other sexually transmitted infections.
Dosing, Administration and Missed Dose Instructions
Advise women to take TYBLUME in one of two ways: (1) swallow whole on an empty stomach or (2) chew and then immediately swallow with a full glass of 240 mL water on an empty stomach. Advise women to take one tablet daily by mouth at the same time every day [see Dosage and Administration (2.1)].
Advise women about what to do in the event tablets are missed. See "What should I do if I miss any TYBLUME tablets" section in FDA-approved patient labeling [see Dosage and Administration (2.3)].
Need for Additional Contraception
CHCs may reduce breast milk production; this is less likely to occur if breastfeeding is well established [see Use in Specific Populations (8.2)] .
Amenorrhea and Possible Symptoms of Pregnancy
Advise women that amenorrhea may occur. Advise women to contact their health care provider in the event of amenorrhea in two or more consecutive cycles or in case of symptoms of pregnancy such as morning sickness or unusual breast tenderness [see Warnings and Precautions (5.8)] .
Advise women that irregular bleeding and/or spotting may occur. Bleeding irregularities typically resolve after the first few months of use. Advise women to consult their healthcare provider if bleeding irregularities persist for more than three to four months [see Warnings and Precautions (5.8)] .
Manufactured for: Exeltis USA, Inc., 180 Park Avenue, Suite 101, Florham Park, NJ 07932
Manufactured by: Laboratorios León Farma, S.A., León, Poligono Industrial Navatejera
C/ La Vallina, s/n 24008 Navatejera, Leon, Spain 24008
|This Patient Information has been approved by the U.S. Food and Drug Administration.||Revised: May 2020|
TYBLUME [tye bloom]
(levonorgestrel and ethinyl estradiol tablets) for oral use
|What is the most important information I should know about TYBLUME (a type of birth control pill)?
Do not use TYBLUME if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects (heart and blood vessel problems) from birth control, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke.
|What is TYBLUME?
|How does TYBLUME 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 one clinical study of a 28-day regimen of levonorgestrel 0.1mg/ethinyl estradiol 0.02 mg tablets, about 1 out of 100 women may get pregnant within the first year they use TYBLUME.
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.
|Do not take TYBLUME if you:
|Before you take TYBLUME, tell your healthcare provider about all of your medical conditions, including if you:
TYBLUME may affect the way other medicines work, and other medicines may affect how well TYBLUME works.
Women on thyroid replacement therapy or steroid therapy may need increased doses of thyroid hormone or steroid medicines.
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 TYBLUME?
|What are the possible side effects of TYBLUME?
TYBLUME may cause serious side effects, including:
|These are not all the possible side effects of TYBLUME. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
|What else should I know about taking TYBLUME?
|How should I store TYBLUME?
|General information about the safe and effective use of TYBLUME.
Medicines are sometimes prescribed for purposes other than those listed in Patient Information. Do not use TYBLUME for a condition for which it was not prescribed. Do not give TYBLUME to other people, even if they have the same symptoms that you have. It may harm them.
You can ask your pharmacist or healthcare provider for information about TYBLUME that is written for health professionals.
Manufactured for: Exeltis USA, Inc., Florham Park, NJ 07932
Manufactured by: Laboratorios León Farma, S.A., León, Spain
Important information about taking TYBLUME (a type of birth control pill):
Before you start taking TYBLUME:
When should I start taking TYBLUME?
If you start taking TYBLUME and you have not used a hormonal birth control method before:
Your healthcare provider should tell you when to start taking your birth control pill.
If you use the Sunday Start, use a non-hormonal back-up birth control method such as condoms or spermicide for the first 7 days that you take TYBLUME. You do not need a back-up birth control method if you use the Day 1 Start.
If you start taking TYBLUME and you are switching from another birth control pill:
If you start taking TYBLUME and previously used a vaginal ring or transdermal patch:
If you start taking TYBLUME and you are switching from a progestin-only method such as an implant or injection:
If you start taking TYBLUME and you are switching from an intrauterine device or system (IUD or IUS):
If you start taking TYBLUME after you have given birth (postpartum) and have not yet had a menstrual period, use an additional method of birth control (such as condoms or spermicide) for the first 7 days that you take TYBLUME.
Keep a calendar to track your menstrual period:
If this is the first time you are taking birth control pills, read, "When should I start taking TYBLUME?" above. Follow these instructions for either a Sunday Start or a Day 1 Start.
You will use a Sunday Start if your healthcare provider told you to take your first pill on a Sunday. Use a non-hormonal back-up birth control method (such as condoms or spermicide) for the first 7 days of the first cycle that you take TYBLUME.
Instructions for using your pill pack:
Day 1 Start:
You will use a Day 1 Start if your healthcare provider told you to take your first pill (Day 1) on the first day of your period.
Instructions for using your pill pack:
Look at your TYBLUME pack. See Figure A.
The TYBLUME pack has:
Find what day of the week you are to start taking your pills. If your period begins on a day other than Sunday, place the day label strip that starts with the first day of your period. For example, if your period begins on Monday, place the day label strip with Monday as the first day. See Figure B.
Remove the white pill by pressing the pill through the foil in the bottom of the pill pack. Continue taking the white pills every day for 21 days.
On the first day of Week 4 start taking the peach pills. Take 1 peach pill every day for 7 days. Your period should start during this time.
When you have taken all of the peach pills in your pill pack, get a new pill pack and start taking the white pills.
What should I do if I miss any TYBLUME tablets?
If you miss 1 white pill in Weeks 1, 2, or 3 of your pill pack, follow these steps:
If you miss 2 white pills in Week 1 or Week 2 of your pill pack, follow these steps:
If you miss 2 white pills in a row in Week 3, or you miss 3 or more white pills in a row during Weeks 1, 2, or 3 of your pill pack, follow these steps:
If you miss 1 or more peach pills in Week 4
If you have any questions or are unsure about the information in this Instructions for Use, call your healthcare provider. You may also read the Patient Information.
Manufactured for: Exeltis USA, Inc., Florham Park, NJ 07932
Manufactured by: Laboratorios León Farma, S.A., León, Spain
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Revised Date: May 2020
(levonorgestrel and ethinyl estradiol) tablets,
0.1 mg/0.02 mg
Contains: 1 blister cards of 28 chewable tablets.
Each blister card contains 21 white tablets each containing 0.1 mg levonorgestrel
and 0.02 mg ethinyl estradiol, and 7 peach inert tablets. Contains lactose.
R x only Oral use
levonorgestrel and ethinyl estradiol kit
|Labeler - Exeltis USA, Inc. (071170534)|
|Registrant - Exeltis USA, Inc. (071170534)|
|Laboratorios Leon Farma S.A.||467782459||manufacture(0642-7471) , analysis(0642-7471) , pack(0642-7471) , label(0642-7471)|