Included as part of the PRECAUTIONS section.
Thromboembolic Disorders And Other Vascular Conditions
Women are at increased risk for a venous thromboembolic event (VTE) when using CHCs, including TWIRLA. The risk of VTE may be greater in women with a BMI ≥ 30 kg/m² compared to women with a lower BMI, and TWIRLA is contraindicated in obese patients [see CONTRAINDICATIONS]. In the Phase 3 clinical trial, four TWIRLA-treated women experienced a VTE. All of these women had a BMI > 30 kg/m² [see ADVERSE REACTIONS].
- Stop TWIRLA if an arterial or venous thromboembolic event occurs.
- Stop TWIRLA if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.
- Discontinue TWIRLA during prolonged immobilization and resume treatment based on clinical judgement. If feasible, stop TWIRLA at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.
- Start TWIRLA no earlier than four weeks after delivery in women who are not breast-feeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week.
- Before starting TWIRLA, evaluate any past medical history or family history of thromboembolism or thromboembolic disorders. Consider whether the history suggests an inherited or acquired hypercoagulopathy. TWIRLA is contraindicated in women with a high risk of arterial or venous thromboembolic diseases [see CONTRAINDICATIONS].
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 women with hypertension, dyslipidemia, diabetes, or obesity.
TWIRLA 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.
The use of CHCs increases the risk of 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. While the increased risk of VTE associated with the use of CHCs is well-established, the rates of VTE are even greater during pregnancy, especially during the postpartum period (see Figure 1). The rate of VTE in women using CHCs has been estimated to be 3 to 12 cases per 10,000 woman-years for non-oral CHCs.
The risk of VTE is highest during the first year of use of a COC and when restarting hormonal contraception after a break of four weeks or longer. This initial higher risk declines during the first year, but users of CHCs remain at an increased risk of VTE compared to non-users of CHCs. 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 women who are not pregnant and do not use hormonal contraceptives, for women who use hormonal contraceptives with a range of doses and routes of administration, for pregnant women, and for women in the postpartum period. To put the risk of developing a VTE into perspective:
If 10,000 women who are not pregnant and do not use hormonal contraceptives are followed for one year, between 1 and 5 of these women will develop a VTE.
Figure 1: Likelihood of Developing a VTE Within One Year Among Pregnant and Non-Pregnant Women
*CHC = combination hormonal contraception
** Pregnancy data based on actual duration of pregnancy in the reference studies. Based on a model assumption that pregnancy duration is 9 months, the rate is 7 to 27 per 10,000 WY.
Elevated Liver Enzymes
TWIRLA is contraindicated in women with acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see CONTRAINDICATIONS]. Discontinue TWIRLA 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.
TWIRLA is contraindicated in women 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.
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 CHCs. CHCs, such as TWIRLA, are contraindicated for use with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir[see CONTRAINDICATIONS]. Discontinue TWIRLA prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. TWIRLA can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.
TWIRLA is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see CONTRAINDICATIONS]. For all women, including those with well-controlled hypertension, monitor blood pressure at routine visits and stop TWIRLA if blood pressure rises significantly.
An increase in blood pressure has been reported in women 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 women, are contraindications to use in women over 35 years of age [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. Consider the presence of underlying risk factors that may increase the risk of cardiovascular disease or VTE, particularly before initiating a CHC for women over 35 years, such as:
Studies suggest an increased risk of developing gallbladder disease among CHC users. Use of CHCs may also worsen existing gallbladder disease.
A past history of CHC-related cholestasis predicts an increased risk with subsequent CHC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for CHC-related cholestasis.
Adverse Carbohydrate And Lipid Metabolic Effects
TWIRLA is contraindicated in diabetic women over age 35, or women who have diabetes with hypertension, nephropathy, retinopathy, neuropathy, other vascular disease, or women with diabetes of > 20 years duration [see CONTRAINDICATIONS]. TWIRLA may decrease glucose tolerance. Carefully monitor prediabetic and diabetic women who are using TWIRLA.
Consider alternative contraception for women with uncontrolled dyslipidemia. TWIRLA may cause adverse lipid changes.
Women with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using TWIRLA, which may increase the risk of pancreatitis.
TWIRLA is contraindicated in women 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 TWIRLA develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue TWIRLA if indicated. Consider discontinuation of TWIRLA if there is any increased frequency or severity of migraines during CHC use (which may be prodromal of a cerebrovascular event).
Bleeding Irregularities And Amenorrhea
Unscheduled And Scheduled Bleeding And Spotting
Women using TWIRLA 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 on TWIRLA, evaluate for causes such as pregnancy or malignancy.
Based on womenâ€™s electronic diaries from a clinical trial evaluating the safety and efficacy of TWIRLA, the proportion of subjects reporting unscheduled bleeding per 28-day cycle decreased over time. At cycle 1 and 2 60.4% and 52.6%, respectively reported unscheduled bleeding and/or spotting. At cycle 13, 42.3% of women reported unscheduled bleeding and/or spotting. Women reported a mean number of unscheduled bleeding/spotting days per month that generally decreased over the 13 cycles and was a mean of 1.6 days in Cycle 13. A total of 45 women (2.2%) discontinued the study prematurely due to menstrual disorders including metrorrhagia, vaginal hemorrhage, menorrhagia, dysmenorrhea, irregular menstruation, dysfunctional uterine bleeding, and menstrual disorder [see Clinical Trial Experience and Clinical Studies].
Amenorrhea And Oligomenorrhea
Women who use TWIRLA may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant. Based on electronic patient diaries from the clinical trial, the percentages of women with no bleeding and/or spotting days (amenorrhea) in a cycle ranged from 11.9% in Cycle 1 to 6.3% in Cycle 13 [see Clinical Trial Experience and Clinical Studies].
If scheduled bleeding does not occur, consider the possibility of pregnancy. If the woman has not adhered to the prescribed dosing schedule (missed days of active therapy or started her TDS 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 woman has adhered to the prescribed dosing schedule and misses two consecutive periods, rule out pregnancy.
After discontinuation of TWIRLA, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent.
Carefully observe women with a history of depression and discontinue TWIRLA 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.
Effect On Binding Globulins
The estrogen component of TWIRLA 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 women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.
Chloasma may occur with TWIRLA use, especially in women with a history of chloasma gravidarum. Advise women with a history of chloasma to avoid exposure to the sun or ultraviolet radiation while using TWIRLA.
Patient Counseling Information
Advise the woman to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).
Advise the woman that cigarette smoking increases the risk of serious cardiovascular events from CHC use. Women who are over 35 years old and smoke should not use TWIRLA [see BOXED WARNING and WARNINGS AND PRECAUTIONS].
Advise the woman that there is an 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 interruption in intake) the same or a different.
Use During Pregnancy
TWIRLA is not to be used during pregnancy. Instruct the woman to stop TWIRLA if pregnancy is confirmed during treatment [see CONTRAINDICATIONS].
Sexually Transmitted Infections
Advise the woman that TWIRLA does not protect against HIV infection and other sexually transmitted infections.
Missed Dosing Instructions
Apply one TDS weekly for 3 weeks followed by one TDS free week. Instruct women what to do in the event TDS change is missed. See “What if you forget to change your TDS or left your TDS on more than 7 days” and “What if you forget to remove your TDS for the TDS free period” in the FDA-approved patient labeling [see DOSAGE AND ADMINISTRATION].
Need For Additional Contraception
Postpartum women who have not yet had a period when they start TWIRLA need to use an additional method of contraception until they have used the TDS for one week [see DOSAGE AND ADMINISTRATION].
A back-up or alternative method of contraception is needed when enzyme inducers are used with TWIRLA [see DRUG INTERACTIONS].
TWIRLA may reduce breast milk production. This is less likely to occur if breast-feeding is well established. When possible, nursing women should use other methods of contraception until they have discontinued breastfeeding [see Use In Specific Populations].
Amenorrhea And Possible Symptoms Of Pregnancy
Amenorrhea may occur. Advise the woman to contact a 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].
Fertility Following Discontinuation Of TWIRLA
Resumption of fertility after discontinuing TWIRLA is expected.
Avoidance Of TDS Detachment
Advise women to avoid frequent or prolonged water exposure (e.g., swimming) and also to avoid use of large amounts of body lotions or oils. Advise women to check the TDS for partial or complete TDS detachment not only daily but also after frequent or prolonged water exposure.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
[see WARNINGS AND PRECAUTIONS, and Pregnancy]
Use In Specific Populations
TWIRLA is contraindicated in pregnancy because there is no reason to use CHCs in pregnancy. Discontinue TWIRLA if pregnancy occurs. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to 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 2â€“4% and 15â€“20%, respectively.
Contraceptive hormones and/or metabolites are present in human milk. CHCs can reduce milk production in breastfeeding women. This reduction can occur at any time but is less likely to occur once breastfeeding is well established. Advise the nursing woman to use another method of contraception until she discontinues breastfeeding [see DOSAGE AND ADMINISTRATION].
No studies have been conducted on the use of TWIRLA in breastfeeding women.
The safety and effectiveness of TWIRLA as a method of contraception have been established in females of reproductive potential with a BMI < 30 kg/m². Efficacy is expected to be the same in postmenarcheal females regardless of age. TWIRLA is not indicated in females before menarche.
TWIRLA has not been studied in postmenopausal women and is not indicated in this population.
No studies have been conducted to evaluate the effect of hepatic impairment on the disposition of TWIRLA. However, steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of CHC use until markers of liver function return to normal and CHC causation has been excluded [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
Body Mass Index (BMI)
Compared to women with a lower BMI, women with a BMI ≥ 30 kg/m² had reduced effectiveness and may have a higher risk for VTEs. Therefore, TWIRLA is contraindicated in women with a BMI ≥ 30 kg/m² [see CONTRAINDICATIONS and Clinical Studies].
TWIRLA has demonstrated reduced efficacy in women with a BMI > 25 and < 30 kg/m² [see Clinical Studies]. Consider this before prescribing TWIRLA to women with a BMI ≥ 25 to < 30 kg/m² .