These Highlights Do Not Include All The Information Needed To Use Tyblume Safely And Effectively. See Full Prescribing Information For Tyblume.

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.

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).

Overdose may cause nausea and uterine bleeding in females.

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.

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:

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.

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).

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.

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

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.

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 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)]

The following serious adverse reactions with the use of CHCs are discussed elsewhere in labeling:

• Serious cardiovascular events [see Boxed Warning and Warnings and Precautions (5.1 and 5.4)]
• Vascular events [see Warnings and Precautions (5.1)]
• Liver disease [see Warnings and Precautions (5.2)]
• Hypertension [see Warnings and Precautions (5.3)]
• Gallbladder disease [see Warnings and Precautions (5.5)]
• Adverse carbohydrate and lipid metabolic effects [see Warnings and Precautions (5.6)]
• Headache [see Warnings and Precautions (5.7)]
• Bleeding irregularities and amenorrhea [see Warnings and Precautions (5.8)]
• Depression [see Warnings and Precautions (5.9)]
• Cervical cancer [see Warnings and Precautions (5.10)]
• Effect on binding globulins [see Warnings and Precautions (5.11)]
• Hereditary angioedema [see Warnings and Precautions (5.12)]
• Chloasma [see Warnings and Precautions (5.13)]
• Risk of liver enzyme elevations with concomitant hepatitis C treatment [see Warnings and Precautions (5.14)]

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.

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.

Important information about taking TYBLUME (a type of birth control pill):

• Take 1 pill every day at the same time. Take the pills in the order directed on your blister pack.
• You may either chew 1 pill and then swallow it with a full 8oz (240mL) glass of water right away, or swallow the pill whole. Take the pill without food (on an empty stomach). Take the white pills and the peach pills the same way.
• Do not skip your pills, even if you do not have sex often. If you miss pills (including starting the pack late) you could get pregnant. The more pills you miss, the more likely you are to get pregnant.
• If you have trouble remembering to take TYBLUME, talk to your healthcare provider. When you first start taking TYBLUME, spotting or light bleeding in between your periods may occur. Contact your healthcare provider if this does not go away after a few months.
• You may feel sick to your stomach (nauseous), especially in the first few months after starting TYBLUME. If you feel sick to your stomach, do not stop taking TYBLUME. The nausea will usually go away. If your nausea does not go away, call your healthcare provider.
• Missing pills can also cause spotting or light bleeding in between your menstrual periods, even when you take the missed pills later. On the days you take 2 pills to make up for missed pills (see " What should I do if I miss any TYBLUME tablets?" ), you could also feel sick to your stomach.
• Some women miss periods on hormonal birth control, even when they are not pregnant. However, if you miss a period and have not taken TYBLUME according to the directions, or miss 2 or more periods in a row, or feel like you may be pregnant, call your healthcare provider. If you have a positive pregnancy test, you should stop taking TYBLUME.
• If you have vomiting or diarrhea within 3 to 4 hours of taking your pill, take another pill of the same color (that was originally scheduled for you to take the next day) from your blister pack. If you miss more than 2 pills, see " What should I do if I miss any TYBLUME tablets?"
  • Continue to take all of your remaining pills in order. Start the first pill of your next blister pack the day after you finish your current blister pack. This will be 1 day earlier than originally scheduled. Continue on your new schedule.

Before you start taking TYBLUME:

• Decide what time of day you want to take your pill. It is important to take it at the same time every day and in the order as directed on your blister pack.
• Have non-hormonal backup birth control (such as condoms or spermicide) available and an extra full pack of pills as needed.

When should I start taking TYBLUME?

If you start taking TYBLUME and you have not used a hormonal birth control method before:

• There are 2 ways to start taking your birth control pills.
  • You can either start on a Sunday (Sunday Start) after you period starts, or
  • You can start on the first day (Day 1) of your natural menstrual period (Day 1 Start).

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:

• Start your new TYBLUME pack on the same day that you would start the next pack of your previous birth control method.
• Do not continue taking the pills from your previous birth control pack.

If you start taking TYBLUME and previously used a vaginal ring or transdermal patch:

• Start using TYBLUME on the day you would have reapplied the next 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:

• Start taking TYBLUME on the day of removal of your implant or on the day when you would have had your next injection.

If you start taking TYBLUME and you are switching from an intrauterine device or system (IUD or IUS):

• Start taking TYBLUME on the day of removal of your IUD or IUS.
• You do not need a back-up birth control method if your IUD or IUS is removed on the first day (Day 1) of your period. If your IUD or IUS is removed on any other day, use a non-hormonal back-up birth control method such as condoms or spermicide for the first 7 days that you take TYBLUME

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.

Sunday 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:

• Look at your TYBLUME pack. See Figure A.
• Take pill 1 on the Sunday after your period starts.
• If your period starts on a Sunday, take pill "1" that day and see " Day 1 Start " instructions below.
• Take 1 pill every day in the order on the blister pack at the same time each day for 28 days.
• After taking the last pill on Day 28 from the blister pack, start taking the first pill from a new pack, on the same day of the week as the first pack (Sunday). Take the first pill in the new pack whether or not you are having your period.

Figure A

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.

• Take 1 pill every day in the order of the blister pack, at the same time each day, for 28 days.
• After taking the last pill on Day 28 from the blister pack, start taking the first pill from a new pack, on the same day of the week as the first pack. Take the first pill in the new pack whether or not you are having your period.

Instructions for using your pill pack:

Step 1.

Look at your TYBLUME pack. See Figure A .

The TYBLUME pack has:

• 21 white (active) tablets (pills) with hormones for Week 1 through Week 3
• 7 peach (inactive) tablets (pills) without hormones for Week 4

Step 2.

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 .

Figure B

Step 3.

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.

Step 4.

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.

Step 5.

When you have taken all of the peach pills in your pill pack, get a new pill pack and start taking the white pills.

• For a Day 1 start:
  
  Begin your next pill pack on the same day of the week as your first cycle pill pack.
• For a Sunday Start:
  
  Begin your next pill pack on Sunday.

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:

• Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day.
• Then continue taking 1 pill every day until you finish the pack.
• You do not need to use a non-hormonal back-up birth control method if you have sex.

If you miss 2 white pills in Week 1 or Week 2 of your pill pack, follow these steps:

• Take 2 pills as soon as possible. Then, take 2 pills the next day. This means you will take 4 pills in 2 days.
• Then continue to take 1 pill every day until you finish the pack.
• Use a non-hormonal back-up birth control method (such as a condom or spermicide) if you have sex during the first 7 days after missing your pills.

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 are a Day 1 Starter:
  • Throw away the rest of the pill pack and start a new pack that same day.
• If you are a Sunday Starter:
  • Keep taking 1 white pill every day until Sunday. On Sunday, throw away the rest of the pack and start a new pack of pills that same day.
• You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your healthcare provider because you might be pregnant.
• You could become pregnant if you have sex during the first 7 days after you restart your pills. You should use a non-hormonal birth control method (such as a condom or spermicide) as a back-up if you have sex during the first 7 days after you restart your pills.

If you miss 1 or more peach pills in Week 4

• Throw away the missed pills.
• Keep taking 1 pill every day until you finish the pack.
• You do not need to use a non-hormonal back-up birth control method (such as condoms or spermicide).
• Make sure you start your next pack on time.

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

No specific pharmacodynamics studies were conducted with TYBLUME.

Data on differences in safety and effectiveness (if any) of TYBLUME between patients with high BMI and lower BMI are not available.

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

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.

CHCs lower the risk of becoming pregnant primarily by suppressing ovulation.

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.

• 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)

In females with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

• 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)

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.

• Lactation: Advise use of another method; TYBLUME can decrease milk production. ( 8.2)

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

The use of CHCs may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

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.

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

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

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).

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.

[see Warnings and Precautions (5.10)]

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)].

Table 4 provides significant drug interaction information for drugs co-administered with TYBLUME.

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)].

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.

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.

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.

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).

Overdose may cause nausea and uterine bleeding in females.

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.

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:

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.

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).

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.

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

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.

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 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)]

The following serious adverse reactions with the use of CHCs are discussed elsewhere in labeling:

• Serious cardiovascular events [see Boxed Warning and Warnings and Precautions (5.1 and 5.4)]
• Vascular events [see Warnings and Precautions (5.1)]
• Liver disease [see Warnings and Precautions (5.2)]
• Hypertension [see Warnings and Precautions (5.3)]
• Gallbladder disease [see Warnings and Precautions (5.5)]
• Adverse carbohydrate and lipid metabolic effects [see Warnings and Precautions (5.6)]
• Headache [see Warnings and Precautions (5.7)]
• Bleeding irregularities and amenorrhea [see Warnings and Precautions (5.8)]
• Depression [see Warnings and Precautions (5.9)]
• Cervical cancer [see Warnings and Precautions (5.10)]
• Effect on binding globulins [see Warnings and Precautions (5.11)]
• Hereditary angioedema [see Warnings and Precautions (5.12)]
• Chloasma [see Warnings and Precautions (5.13)]
• Risk of liver enzyme elevations with concomitant hepatitis C treatment [see Warnings and Precautions (5.14)]

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.

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.

Important information about taking TYBLUME (a type of birth control pill):

• Take 1 pill every day at the same time. Take the pills in the order directed on your blister pack.
• You may either chew 1 pill and then swallow it with a full 8oz (240mL) glass of water right away, or swallow the pill whole. Take the pill without food (on an empty stomach). Take the white pills and the peach pills the same way.
• Do not skip your pills, even if you do not have sex often. If you miss pills (including starting the pack late) you could get pregnant. The more pills you miss, the more likely you are to get pregnant.
• If you have trouble remembering to take TYBLUME, talk to your healthcare provider. When you first start taking TYBLUME, spotting or light bleeding in between your periods may occur. Contact your healthcare provider if this does not go away after a few months.
• You may feel sick to your stomach (nauseous), especially in the first few months after starting TYBLUME. If you feel sick to your stomach, do not stop taking TYBLUME. The nausea will usually go away. If your nausea does not go away, call your healthcare provider.
• Missing pills can also cause spotting or light bleeding in between your menstrual periods, even when you take the missed pills later. On the days you take 2 pills to make up for missed pills (see " What should I do if I miss any TYBLUME tablets?" ), you could also feel sick to your stomach.
• Some women miss periods on hormonal birth control, even when they are not pregnant. However, if you miss a period and have not taken TYBLUME according to the directions, or miss 2 or more periods in a row, or feel like you may be pregnant, call your healthcare provider. If you have a positive pregnancy test, you should stop taking TYBLUME.
• If you have vomiting or diarrhea within 3 to 4 hours of taking your pill, take another pill of the same color (that was originally scheduled for you to take the next day) from your blister pack. If you miss more than 2 pills, see " What should I do if I miss any TYBLUME tablets?"
  • Continue to take all of your remaining pills in order. Start the first pill of your next blister pack the day after you finish your current blister pack. This will be 1 day earlier than originally scheduled. Continue on your new schedule.

Before you start taking TYBLUME:

• Decide what time of day you want to take your pill. It is important to take it at the same time every day and in the order as directed on your blister pack.
• Have non-hormonal backup birth control (such as condoms or spermicide) available and an extra full pack of pills as needed.

When should I start taking TYBLUME?

If you start taking TYBLUME and you have not used a hormonal birth control method before:

• There are 2 ways to start taking your birth control pills.
  • You can either start on a Sunday (Sunday Start) after you period starts, or
  • You can start on the first day (Day 1) of your natural menstrual period (Day 1 Start).

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:

• Start your new TYBLUME pack on the same day that you would start the next pack of your previous birth control method.
• Do not continue taking the pills from your previous birth control pack.

If you start taking TYBLUME and previously used a vaginal ring or transdermal patch:

• Start using TYBLUME on the day you would have reapplied the next 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:

• Start taking TYBLUME on the day of removal of your implant or on the day when you would have had your next injection.

If you start taking TYBLUME and you are switching from an intrauterine device or system (IUD or IUS):

• Start taking TYBLUME on the day of removal of your IUD or IUS.
• You do not need a back-up birth control method if your IUD or IUS is removed on the first day (Day 1) of your period. If your IUD or IUS is removed on any other day, use a non-hormonal back-up birth control method such as condoms or spermicide for the first 7 days that you take TYBLUME

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.

Sunday 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:

• Look at your TYBLUME pack. See Figure A.
• Take pill 1 on the Sunday after your period starts.
• If your period starts on a Sunday, take pill "1" that day and see " Day 1 Start " instructions below.
• Take 1 pill every day in the order on the blister pack at the same time each day for 28 days.
• After taking the last pill on Day 28 from the blister pack, start taking the first pill from a new pack, on the same day of the week as the first pack (Sunday). Take the first pill in the new pack whether or not you are having your period.

Figure A

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.

• Take 1 pill every day in the order of the blister pack, at the same time each day, for 28 days.
• After taking the last pill on Day 28 from the blister pack, start taking the first pill from a new pack, on the same day of the week as the first pack. Take the first pill in the new pack whether or not you are having your period.

Instructions for using your pill pack:

Step 1.

Look at your TYBLUME pack. See Figure A .

The TYBLUME pack has:

• 21 white (active) tablets (pills) with hormones for Week 1 through Week 3
• 7 peach (inactive) tablets (pills) without hormones for Week 4

Step 2.

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 .

Figure B

Step 3.

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.

Step 4.

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.

Step 5.

When you have taken all of the peach pills in your pill pack, get a new pill pack and start taking the white pills.

• For a Day 1 start:
  
  Begin your next pill pack on the same day of the week as your first cycle pill pack.
• For a Sunday Start:
  
  Begin your next pill pack on Sunday.

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:

• Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day.
• Then continue taking 1 pill every day until you finish the pack.
• You do not need to use a non-hormonal back-up birth control method if you have sex.

If you miss 2 white pills in Week 1 or Week 2 of your pill pack, follow these steps:

• Take 2 pills as soon as possible. Then, take 2 pills the next day. This means you will take 4 pills in 2 days.
• Then continue to take 1 pill every day until you finish the pack.
• Use a non-hormonal back-up birth control method (such as a condom or spermicide) if you have sex during the first 7 days after missing your pills.

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 are a Day 1 Starter:
  • Throw away the rest of the pill pack and start a new pack that same day.
• If you are a Sunday Starter:
  • Keep taking 1 white pill every day until Sunday. On Sunday, throw away the rest of the pack and start a new pack of pills that same day.
• You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your healthcare provider because you might be pregnant.
• You could become pregnant if you have sex during the first 7 days after you restart your pills. You should use a non-hormonal birth control method (such as a condom or spermicide) as a back-up if you have sex during the first 7 days after you restart your pills.

If you miss 1 or more peach pills in Week 4

• Throw away the missed pills.
• Keep taking 1 pill every day until you finish the pack.
• You do not need to use a non-hormonal back-up birth control method (such as condoms or spermicide).
• Make sure you start your next pack on time.

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

No specific pharmacodynamics studies were conducted with TYBLUME.

Data on differences in safety and effectiveness (if any) of TYBLUME between patients with high BMI and lower BMI are not available.

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

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.

CHCs lower the risk of becoming pregnant primarily by suppressing ovulation.

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.

• 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)

In females with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

• 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)

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.

• Lactation: Advise use of another method; TYBLUME can decrease milk production. ( 8.2)

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

The use of CHCs may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

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.

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

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

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).

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.

[see Warnings and Precautions (5.10)]

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)].

Table 4 provides significant drug interaction information for drugs co-administered with TYBLUME.

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)].

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.

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.