DailyMed Label: Tyblume

DailyMed Label: Tyblume

2023

DailyMed Prescription

Tyblume

Levonorgestrel and Ethinyl Estradiol

Exeltis USA, Inc.

NDC: 0642-7471

NDC: 0642-7471

NDC: 0642-7471

NDC: 0642-7471

NDC: 0642-7471

NDC: 0642-7471

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 21 H 28 O 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 20 H 24 O 2 , the molecular weight of 296.4, and the structural formula is provided below: Chemical Structure Chemical Structure

TYBLUME is indicated for use by females of reproductive potential to prevent pregnancy. 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 )

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. ( 2.1 ) Start on Day 1 and take each tablet at the same time every day in the order directed on the blister pack, or ( 2 ) Start on a Sunday and take each tablet at the same time every day in the order directed on the blister pack. ( 2 ) Take 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. ( 2 ) 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 ). Table 1 Instructions for Administration of TYBLUME Starting TYBLUME in females with no current use of hormonal contraception (start on Day 1 or Sunday) Day 1 start Take first tablet without food (i.e. empty stomach) on the first day of menses Take subsequent tablets once daily at the same time each day Begin each subsequent 28-day pack on the same day of the week as the first cycle pack (i.e., on the day after taking the last tablet) Sunday start Take first tablet without food (i.e. empty stomach) on the first Sunday after the onset of menstrual period Take subsequent tablets once daily at the same time each day Use additional nonhormonal contraception for the first seven days of TYBLUME use Begin each subsequent 28-day pack on the same day of the week as the first cycle pack (i.e., on the day after taking the last tablet) Switching to TYBLUME from another contraceptive method Start TYBLUME: A combined oral contraceptive (COC) On the day when the new pack of the previous COC would have been started Transdermal system On the day when next application would have been scheduled Vaginal ring On the day when next insertion would have been scheduled Injection On the day when next injection would have been scheduled Intrauterine system On the day of removal Implant On the day of removal 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). Table 2 Instructions for Missed TYBLUME If one white active tablet is missed in Weeks 1, 2, or 3 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. If two white active tablets are missed in Week 1 or Week 2 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. If two white active tablets are missed in the third week or three or more active tablets are missed in a row in Weeks 1, 2, or 3 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. If one or more peach (inactive) tablets are missed in the fourth week 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: 21 active tablets are white, round, and debossed with 30 on one side and L2 on the other side. Each active tablet contains levonorgestrel 0.1 mg and ethinyl estradiol 0.02 mg. 7 inactive tablets (placebo) are peach-colored, round, and debossed with 1 on one side and L2 on the other side. A TYBLUME pack consists of 28 tablets: 21 white tablets (active), each containing levonorgestrel 0.1 mg and ethinyl estradiol 0.02 mg. 7 peach-colored tablets (inactive placebo).

TYBLUME is contraindicated in females who are known to have 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 (5.3) ] Have diabetes mellitus and are over age 35, diabetes mellitus with hypertension or vascular disease or other end-organ damage, or diabetes mellitus of > 20 years duration [see Warnings and Precautions (5.6) ] Have headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches [see Warnings and Precautions (5.7) ] Current or history of breast cancer or other estrogen- or progestin-sensitive cancer Liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis [see Warnings and Precautions (5.2) ] Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.8) ] 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 (5.14) ] High risk of arterial or venous thrombotic diseases. ( 4 ) Breast cancer or other estrogen- or progestin-sensitive cancer. ( 4 ) Liver tumors, acute viral hepatitis or decompensated cirrhosis. ( 4 ) Undiagnosed abnormal uterine bleeding. ( 4 ) Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. ( 4 )

Vascular risks : Stop if a thrombotic or thromboembolic event occurs. Stop TYBLUME at least 4 weeks before and through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in females who are not breast-feeding. Consider cardiovascular risk factors before initiating in all females, particularly those over 35 years. ( 5.1 , 5.4 ) Liver disease : Discontinue TYBLUME if jaundice occurs. ( 5.2 ) Hypertension : If used in females with well-controlled hypertension, monitor blood pressure. Stop use of TYBLUME if blood pressure rises significantly. ( 5.3 ) Gallbladder disease : May cause or worsen gallbladder disease. ( 5.5 ) Adverse carbohydrate and lipid effect : Monitor glucose in prediabetic and diabetic females using TYBLUME. Consider an alternate contraceptive method for females with uncontrolled dyslipidemia. ( 5.6 ) Headache : Evaluate significant change in headaches and discontinue TYBLUME if indicated. ( 5.7 ) Uterine bleeding : May cause irregular bleeding or amenorrhea. Evaluate for other causes if symptoms persist. ( 5.8 ) 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) ]. Stop TYBLUME if an arterial or venous thrombotic/thromboembolic event occurs. Stop TYBLUME if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately. Discontinue TYBLUME during prolonged immobilization. If feasible, stop TYBLUME at least four weeks before and through two weeks after major surgery, or other surgeries known to have an elevated risk of thromboembolism. Start TYBLUME no earlier than four 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. Arterial Events 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. Venous Events 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 Figure 1 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. Liver Tumors 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: Hypertension Diabetes Dyslipidemia Obesity 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. Hyperglycemia 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. Dyslipidemia 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 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. 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 ) Substances decreasing the Plasma Concentration of CHCs and Potentially Diminishing the Efficacy of CHCs Table 3 Significant Drug Interactions Involving Substances That Affect CHCs a Induction potency of St. John's wort may vary widely based on preparation. Metabolic Enzyme Inducers Clinical effect Concomitant use of CHCs with metabolic enzyme inducers may decrease the plasma concentrations of the estrogen and/or progestin component of CHCs [see Clinical Pharmacology (12.3) ] . Decreased exposure of the estrogen and/or progestin component of CHCs may potentially diminish the effectiveness of CHCs 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 CHCs. 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, primidone, phenylbutazone, rifabutin, rufinamide, topiramate, products containing St. John's wort, and certain protease inhibitors (see separate section on protease inhibitors below). Colesevelam Clinical effect Concomitant use of CHCs with colesevelam significantly decreases systemic exposure of ethinyl estradiol [see Clinical Pharmacology (12.3) ]. Decreased exposure of the estrogen component of CHCs may potentially reduce contraceptive efficacy or result in an increase in breakthrough bleeding, depending on the strength of ethinyl estradiol in the CHC. 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 The effect of grapefruit juice on CYP3A4 enzymes (e.g., strong vs. moderate inhibition) depends on its brand, concentration, and preparation. , 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. Table 4 Significant Drug Interaction Information for Drugs Co-Administered with CHCs Lamotrigine Clinical effect Concomitant use of CHCs 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 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) ]. Other Drugs 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.

Lactation : Advise use of another method; TYBLUME can decrease milk production. ( 8.2 ) Risk Summary 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. Risk Summary 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. Data 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) ] . Data on differences in safety and effectiveness (if any) of TYBLUME between patients with high BMI and lower BMI are not available.

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 side. NDC 0642-7471-01, one carton containing 1 individual blister card Store at controlled room temperature 20°C to 25°C (68°F to 77°F). Excursions are NOT permitted. Protect from light and excessive heat.

CHCs lower the risk of becoming pregnant primarily by suppressing ovulation. No specific pharmacodynamics studies were conducted with TYBLUME. Absorption 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. Table 5 Summary Mean (CV%) Pharmacokinetic Parameters from Single Dose Administration of TYBLUME Analyte Sample Size C max (pg/mL) T max (h) Median (min – max) AUC 0-T (pg*h/mL) AUC 0-∞ (pg*h/mL) T 1/2 (h) 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 n = 30 for AUC 0-∞ and T 1/2 3225.0 (33.1) 0.75 (0.50-1.00) 27586.0 (39.0) 34099.0 (36.8) 33.67 (31.8) Distribution 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. Elimination Metabolism 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. Excretion 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.

[see Warnings and Precautions (5.10) ]

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.

This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: May 2020 PATIENT INFORMATION 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? TYBLUME is a birth control pill (oral contraceptive) used by women to prevent pregnancy. TYBLUME does not protect against HIV infections (AIDS) and other sexually transmitted infections. 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: smoke and are over 35 years of age. have or have had blood clots in your arms, legs, lungs, or eyes. have a problem with your blood that makes it clot more than normal. have certain heart valve problems or an irregular heartbeat that increases your risk of having blood clots. had a stroke. had a heart attack. have high blood pressure that cannot be controlled by medicine or have high blood pressure with blood vessel problems. have diabetes and are over 35 years of age; have diabetes with high blood pressure, blood vessel problems, or kidney, eye, nerve, or blood vessel damage; or have had diabetes for more than 20 years. have certain kinds of severe migraine headaches with aura, numbness, weakness or changes in vision, or any migraine headaches if you are over 35 years of age. have liver problems, including liver tumors. have any unexplained vaginal bleeding. have or have had breast cancer or any cancer that is sensitive to female hormones. take any Hepatitis C drug combination containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. This may increase levels of the liver enzyme "alanine aminotransferase" (ALT) in the blood. If any of these conditions happen while you are taking TYBLUME, stop taking TYBLUME right away and talk to your healthcare provider. Use non-hormonal contraception when you stop taking TYBLUME. Before you take TYBLUME, tell your healthcare provider about all of your medical conditions, including if you: are scheduled for surgery. TYBLUME may increase your risk of blood clots after surgery. You should stop taking TYBLUME at least 4 weeks before you have surgery and not restart TYBLUME until at least 2 weeks after your surgery. are pregnant or think you may be pregnant. are depressed now or have been depressed in the past. had yellowing of your skin or eyes (jaundice) caused by pregnancy (cholestasis of pregnancy). are breastfeeding or plan to breastfeed. TYBLUME may decrease the amount of breast milk you make. A small amount of the hormones in TYBLUME may pass into your breast milk. Talk to your healthcare provider about the best birth control method for you while breastfeeding. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. 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? Read the detailed Instructions for Use at the end of this Patient Information leaflet about the right way to take TYBLUME. Take TYBLUME exactly as your healthcare provider tells you to take it. You may take TYBLUME 1 of 2 ways: Chew TYBLUME and then swallow TYBLUME with a full 8 oz (240 mL) glass of water right away , or Swallow TYBLUME whole. Take TYBLUME on an empty stomach. What are the possible side effects of TYBLUME? TYBLUME 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: first start taking birth control pills. restart the same or different birth control pills after not using them for a month or more. Call your healthcare provider or go to the nearest emergency room right away if you have: leg pain that will not go away. sudden severe shortness of breath. sudden change in vision or blindness. chest pain. a sudden, severe headache unlike our usual headaches. weakness or numbness in your arm or leg. trouble speaking. Other serious side effects include: liver problems, including: jaundice. Call your healthcare provider if you have yellowing of your skin or eyes. rare liver tumors. high blood pressure. You should see your healthcare provider to check your blood pressure regularly. gallbladder problems (cholestasis), especially if you previously had cholestasis of pregnancy. changes in the sugar and fat (cholesterol and triglycerides) levels in your blood. new or worsening headaches including migraine headaches. irregular or unusual vaginal bleeding and spotting between your menstrual periods, especially during the first 3 months of taking TYBLUME or the absence of menstrual periods (amenorrhea). depression. possible cancer in your cervix. swelling of your skin especially around your mouth, eyes, and in your throat (angioedema). Call your healthcare provider right away if you have a swollen face, lips, mouth, tongue or throat, which may lead to difficulty swallowing or breathing. Your chance of having angioedema is higher if you have a history of angioedema. dark patches of skin around your forehead, nose, cheeks and around your mouth, especially during pregnancy (chloasma). Women who tend to get chloasma should avoid spending a long time in sunlight, tanning booths, and under sun lamps while taking TYBLUME. Use sunscreen if you have to be in the sunlight. The most common side effects of TYBLUME include: headache stomach (abdominal) pain nausea vaginal bleeding in between your periods vaginal yeast infection and pain acne infection or swelling of the vagina that can cause discharge, itching, and pain 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? If you are scheduled for any lab tests, tell your healthcare provider you are taking TYBLUME. Certain blood tests may be affected by TYBLUME. How should I store TYBLUME? Store the blister card that TYBLUME comes in at room temperature between 68°F to 77°F (20°C to 25°C). Protect TYBLUME from light. Protect TYBLUME from high heat. Keep TYBLUME and all medicines out of the reach of children. 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 Image

NDC 0642-7471-01 Tyblume™ (levonorgestrel and ethinyl estradiol) tablets, 0.1 mg/0.02 mg CHEWABLE 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 Tyblume carton label