WARNINGS
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS
Thromboembolic Disorders And Other Vascular Problems
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].
- 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]. 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]. 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.
Figure 1 Likelihood of Developing a VTE
 |
*Pregnancy data based on actual duration of pregnancy in the reference studies. Based on a model assumption that pregnancy duration is nine months, the rate is 7 to 27 per 10,000 WY. |
Liver Disease
Elevated Liver Enzymes
TYBLUME is contraindicated in females with acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see CONTRAINDICATIONS]. 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]. 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.
Hypertension
TYBLUME is contraindicated in females with uncontrolled hypertension or hypertension with vascular disease [see CONTRAINDICATIONS]. 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.
Age-Related Considerations
The risk for cardiovascular disease and prevalence of risk factors for cardiovascular disease increase with age. Certain conditions, such as smoking and migraine headache without aura, that do not contraindicate CHC use in younger females, are contraindications to use in women over 35 years of age [see CONTRAINDICATIONS and Thromboembolic Disorders And Other Vascular Problems]. 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
Gallbladder Disease
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.
Adverse Carbohydrate And Lipid Metabolic Effects
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]. 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.
Headache
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].
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).
Bleeding Irregularities And Amenorrhea
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.
Depression
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.
Cervical Cancer
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.
Effect On Binding Globulins
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.
Hereditary Angioedema
In females with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.
Chloasma
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.
Risk Of Liver Enzyme Elevations With Concomitant Hepatitis C Treatment
During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications, such as COCs. COCs are contraindicated for use with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see CONTRAINDICATIONS]. 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.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).
Cigarette Smoking
Advise women that cigarette smoking increases the risk of serious cardiovascular events from CHC use, and that women who are over 35 years old and smoke should not use TYBLUME [see BOX WARNING and WARNINGS AND PRECAUTIONS].
Venous Thromboembolism
Advise women that the increased risk of VTE compared to non-users of CHCs is greatest after initially starting a CHC or restarting (following a 4-week or greater tablet-free interval) the same or a different CHC [see WARNINGS AND PRECAUTIONS].
Use During Pregnancy
Advise women that there is no reason to use TYBLUME during pregnancy. Instruct the woman to stop TYBLUME if pregnancy is confirmed during treatment [see Use In Specific Populations].
Sexually Transmitted Infections
Advise women that TYBLUME does not protect against HIV-infection (AIDS) and other sexually transmitted infections.
Dosing, Administration And Missed Dose Instructions
Advise women to take TYBLUME in one of two ways: (1) swallow whole on an empty stomach or (2) chew and then immediately swallow with a full glass of 240 mL water on an empty stomach. Advise women to take one tablet daily by mouth at the same time every day [see DOSAGE AND ADMINISTRATION].
Advise women about what to do in the event tablets are missed. See “What should I do if I miss any TYBLUME tablets” section in FDA-approved patient labeling [see DOSAGE AND ADMINISTRATION].
Need For Additional Contraception
- Advise women to use a back-up or alternative method of contraception when enzyme inducers are used with TYBLUME [see DRUG INTERACTIONS].
- Advise a woman who starts CHCs postpartum and has not yet had a period that she should use an additional method of contraception until she has taken a white tablet for 7 consecutive days.
Lactation
CHCs may reduce breast milk production; this is less likely to occur if breastfeeding is well established [see Use In Specific Populations].
Amenorrhea And Possible Symptoms Of Pregnancy
Advise women that amenorrhea may occur. Advise women to contact their health care provider in the event of amenorrhea in two or more consecutive cycles or in case of symptoms of pregnancy such as morning sickness or unusual breast tenderness [see WARNINGS AND PRECAUTIONS].
Bleeding Irregularities
Advise women that irregular bleeding and/or spotting may occur. Bleeding irregularities typically resolve after the first few months of use. Advise women to consult their healthcare provider if bleeding irregularities persist for more than three to four months [see WARNINGS AND PRECAUTIONS].
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
[see WARNINGS AND PRECAUTIONS]
Use In Specific Populations
Pregnancy
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.
Lactation
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]. 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.
Pediatric Use
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.
Geriatric Use
TYBLUME has not been studied in postmenopausal women and is not indicated in this population.
Hepatic Impairment
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 and WARNINGS AND PRECAUTIONS].
Body Mass Indexes
Data on differences in safety and effectiveness (if any) of TYBLUME between patients with high BMI and lower BMI are not available.