Twirla by is a Prescription medication manufactured, distributed, or labeled by Agile Therapeutics, Inc.. Drug facts, warnings, and ingredients follow.
Warnings and Precautions (5.11) 04/2022
TWIRLA is a combination of levonorgestrel, a progestin, and ethinyl estradiol, an estrogen, indicated as a method of contraception for use in women of reproductive potential with a BMI < 30 kg/m2 for whom a combined hormonal contraceptive is appropriate. (1)
Limitation of Use
Consider TWIRLA’s reduced effectiveness in women with a BMI ≥ 25 to < 30 kg/m2 before prescribing. (4, 8.9, 14)
Transdermal system: 120 mcg/day levonorgestrel (LNG) and 30 mcg/day ethinyl estradiol (EE) (3)
The most common adverse reactions (≥ 2%) in clinical trials for TWIRLA are application site disorders, nausea, headache, dysmenorrhea, and increased weight. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Agile Therapeutics, Inc. at 1-888-389-4752 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Enzyme inducers (e.g., CYP3A4): May decrease the effectiveness of TWIRLA or increase breakthrough bleeding. Counsel women to use a back-up or alternative method of contraception when enzyme inducers are used with TWIRLA. (7.1)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 4/2022
Cigarette Smoking and Serious Cardiovascular Events
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 TWIRLA, are contraindicated in women who are over 35 years of age and smoke [see Contraindications (4) and Warnings and Precautions (5.1)].
Contraindicated in Women with a BMI ≥ 30 kg/m2
TWIRLA is contraindicated in women with a BMI ≥ 30 kg/m2. Compared to women with a lower BMI, women with a BMI ≥ 30 kg/m2 had reduced effectiveness and may have a higher risk for venous thromboembolism events (VTEs) [see Contraindications (4) and Warnings and Precautions (5.1)].
TWIRLA is indicated as a method of contraception for use in women of reproductive potential with a BMI < 30 kg/m2 for whom a combined hormonal contraceptive is appropriate.
Limitation of Use
Consider TWIRLA’s reduced effectiveness in women with a BMI ≥ 25 to < 30 kg/m2 before prescribing TWIRLA [see Use in Specific Populations (8.9) and Clinical Studies (14)]. TWIRLA is contraindicated in women with a BMI ≥ 30 kg/m2 [see Contraindications (4)].
See the FDA-approved patient labeling (Instructions for Use).
The TWIRLA transdermal system (TDS) is used in a 28-day (four-week) cycle. A new TDS is applied and worn for seven days for three consecutive weeks (Weeks 1, 2, and 3). No TDS is worn during Week 4 (the TDS-Free Week), when withdrawal bleeding is expected.
On the day after Week 4 ends, a new 28-day cycle is started by applying a new TDS. Under no circumstances should there be more than a 7-day TDS-free interval between dosing cycles.
Breakthrough (Unscheduled) Bleeding or Spotting Occurrence
If unscheduled (breakthrough) spotting or bleeding occurs, instruct the woman to continue the same regimen. If the bleeding is persistent or prolonged consider causes other than TWIRLA. If the bleeding is persistent or prolonged, instruct the woman to consult with her healthcare provider.
In Case of Skin Irritation
If TDS use results in uncomfortable irritation, the TDS may be removed, and a new TDS may be applied to a different location until the next “Patch Change Day”. Only one TDS should be worn at a time.
Every new TDS should be applied on the same day of the week. This day is known as the “Patch Change Day.” For example, if the first TDS is applied on a Sunday, all subsequent TDS should be applied on a Sunday.
There are multiple options for starting the TDS, and the woman should choose the option that is most appropriate (see Table 1):
Starting TWIRLA in women with no current use of hormonal contraception |
Day 1 Start
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Switching from another contraceptive method
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Start TWIRLA:
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Use after an abortion or miscarriage:
TWIRLA may be started immediately for contraception within the first 5 days following a complete first trimester abortion or miscarriage without additional back-up contraception. If more than 5 days have elapsed from the first trimester abortion or miscarriage, then the woman should be advised to use non-hormonal contraception (such as condoms and spermicide, or diaphragm and spermicide) and follow instructions for starting TWIRLA for the first time. Ovulation may occur within 10 days of an abortion or miscarriage.
TWIRLA should not be started earlier than 4 weeks after a second trimester abortion or miscarriage due to the increased risk of thromboembolism [see Warnings and Precautions (5.1)].
Use of TWIRLA after childbirth:
For women who elect not to breastfeed, do not start TWIRLA sooner than 4 weeks after childbirth given the increased risk for thromboembolism [see Use in Specific Populations (8.2)].
If a woman begins using TWIRLA postpartum and has not yet had a period, consider the possibility of ovulation and pregnancy. If the woman is not pregnant, instruct her to use non-hormonal back-up contraception (such as condoms and spermicide, or diaphragm and spermicide) for the first 7 days of TDS use [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].
MANAGING PARTIAL OR COMPLETE TDS DETACHMENTS (see Table 2)
The TWIRLA TDS must adhere securely to the skin to work properly. Prolonged water exposure may compromise the TDS’s adherence. As a result, the woman should be instructed to check the TDS for partial or complete TDS detachment not only daily but also after prolonged water exposure.
If the TDS becomes partially or completely detached and remains detached, insufficient drug delivery may occur. Partial TDS detachment should be resolved since it can lead to the TDS getting caught on clothing and detaching. The woman should not try to reapply a TDS if it is no longer sticky, if it has become stuck to itself or another surface, and/or if it has other material stuck to it.
If a TDS edge lifts up:
If the TDS has been off or partially off:
Instruct women about the handling of missed doses (e.g., missed or delayed TDS application) and to follow the dosing instructions provided in the FDA-approved patient labeling.
FORGETTING TO CHANGE THE TDS:
Scenario | Results in New TDS- Change Day | Back-up Contraception Required (7 Days) | Starts New Cycle |
Did not apply TDS on scheduled Day 1/Week 1 of new cycle (late TDS-on day) | Yes | Yes | Yes |
TDS detached for < 24 hours | No | No | No |
TDS detached for ≥ 24 hours, or unsure duration | Yes | Yes | Yes |
< 48 hours late for Patch Change Day (Day 8 or 15) | No | No | No |
≥ 48 hours late for Patch Change Day (Day 8 or 15) | Yes | Yes | Yes |
Forgets to remove last TDS on Day 22 | No | No | No |
Under no circumstances should there be more than a seven-day TDS-free interval between cycles. If there are more than 7 TDS-free days, THE WOMAN MAY NOT BE PROTECTED FROM PREGNANCY and non-hormonal back-up contraception (such as a condoms and spermicide, or diaphragm and spermicide) must be used for 7 days. As with CHCs, the risk of ovulation increases with each day beyond the recommended drug-free period. If the woman has intercourse during such an extended TDS-free interval, consider the possibility of pregnancy.
Twirla is contraindicated in females who are known to have or develop the following 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 (4)]. 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 (6.1)].
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 women with hypertension, dyslipidemia, diabetes, or obesity.
TWIRLA 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
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 combined oral contraceptive (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 (4)]. 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.
Liver Tumors
TWIRLA is contraindicated in women 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.
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 (4)]. 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 (4)]. 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 (4) and Warnings and Precautions (5.1)]. Consider the presence of underlying risk factors that may increase the risk of cardiovascular disease or VTE, particularly before initiating a CHC for women over 35 years, such as:
Studies suggest an increased risk of developing gallbladder disease among CHC users. Use of CHCs may also worsen existing gallbladder disease.
A past history of CHC-related cholestasis predicts an increased risk with subsequent CHC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for CHC-related cholestasis.
Hyperglycemia
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 (4)]. TWIRLA may decrease glucose tolerance. Carefully monitor prediabetic and diabetic women who are using TWIRLA.
Dyslipidemia
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 (4)].
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).
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 women’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 (6.1) and Clinical Studies (14)].
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 6.3% to 11.9% over 13 cycles [see Clinical Trial Experience (6.1) and Clinical Studies (14)].
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.
Breast Cancer
Twirla is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4)].
Epidemiology studies have not found a consistent association between use of COCs and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use [see Postmarketing Experience (6.2)].
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.
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.
The following serious adverse reactions with the use of CHCs, including TWIRLA, are discussed elsewhere in the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of one product cannot be directly compared to rates in the clinical trials of another product and may not reflect the rates observed in practice.
The safety of TWIRLA was evaluated in a 12-month, multicenter, open-label, single-arm clinical trial (NCT02158572) conducted in the United States [see Clinical Studies (14)]. Women applied TWIRLA (120 mcg LNG/30 mcg EE) for 13 28-day treatment cycles. One treatment cycle is defined as three consecutive weeks that one TWIRLA TDS is applied for seven-day wear followed by one week that TWIRLA is not applied.
The safety population for this clinical trial was composed of 2,031 women that contributed 18,841 treatment cycles of exposure. Of these 2,031 women, 989 women completed 13 treatment cycles. The mean age was 27.5 years. The mean BMI for the safety population was 28.3 kg/m2. The BMI of the safety population was widely distributed: 39.4% had a BMI < 25 kg/m2, 25.3% had a BMI ≥ 25 kg/m2 and < 30 kg/m2, and 35.3% had a BMI ≥ 30 kg/m2.
For women who received TWIRLA, the most common reasons for discontinuation from the study were a womans decision (15.3%) and lost to follow-up (11.3%).
Discontinuation due to an adverse reaction occurred in 10.9% of women. The most common (≥ 2%) adverse reactions leading to discontinuation were application site disorder (3.1%) and any bleeding irregularities (2.2%).
The most common adverse reactions that occurred in ≥ 2% of the 2,031 women that used TWIRLA are shown in Table 3.
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Adverse reaction | TWIRLA (n=2,031) |
General disorders and administration site conditions
Application site disorder* | 6.2% |
Gastrointestinal disorders
Nausea | 4.1% |
Nervous system disorders
Headache | 3.6% |
Reproductive system and breast disorder
Dysmenorrhoea | 2.3% |
Investigations
Weight increased | 2.0% |
Venous Thromboembolic Events (VTEs)
A total of four VTEs (including pulmonary embolism and deep vein thrombosis) in TWIRLA-treated patients were identified in the clinical trial. Of these, all were in women with a BMI > 30 kg/m2 [see Contraindications (4)].
Other Serious Adverse Reactions
The following serious adverse reactions occurred in < 1% of women who received TWIRLA: cholelithiasis, cholecystitis, major depression, suicidal ideation, appendicitis, ectopic pregnancy, pneumonia, and gastroenteritis.
Five studies that compared breast cancer risk between ever-users (current or past use) of combined oral contraceptives (COCs) and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 - 1.12 (Figure 2).
Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 2). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19 - 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8-10 years of COC use.
Figure 2. Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives
RR = relative risk; OR = odds ratio; HR = hazard ratio. “ever COC” are females with current or past COC use; “never COC use” are females that never used COCs.
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 TWIRLA.
Substances Decreasing Plasma Concentration of CHCs and Potentially Diminishing the Efficacy of CHCs:
Table 4 includes substances that demonstrated an important drug interaction with TWIRLA.
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Metabolic Enzyme Inducers |
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Clinical effect |
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Prevention or management |
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Examples |
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Colesevelam |
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Clinical effect |
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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. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, 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 5 provides significant drug interaction information for drugs co-administered with TWIRLA.
Lamotrigine |
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Clinical effect |
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Prevention or management |
Dose adjustment may be necessary. Consult the approved product labeling for lamotrigine. |
Thyroid Hormone Replacement Therapy or Corticosteroid Replacement Therapy |
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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 (5.12)]. |
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 (5.12)]. |
Other Drugs |
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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 some 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 Warnings and Precautions (5.4) and Contraindications (4)]. 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.
Risk Summary
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 2–4% and 15–20%, respectively.
Risk Summary
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 (2.1)].
Human Data
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 (4) and Warnings and Precautions (5.2)].
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 (4) and Clinical Studies (14)].
TWIRLA has demonstrated reduced efficacy in women with a BMI ≥ 25 and < 30 kg/m2 [see Clinical Studies (14)]. Consider this before prescribing TWIRLA to women with a BMI ≥ 25 to < 30 kg/m2.
TWIRLA (levonorgestrel and ethinyl estradiol) transdermal system (TDS) contains 2.60 mg levonorgestrel (LNG) (17α)-(–) [13-ethyl-17¬hydroxy-18, 19-dinorpregn-4-en-20-yn-3-one], a progestin, and 2.30 mg ethinyl estradiol (EE), [(17α)-19-norpregna-1, 3, 5(10)-trien-20-yne-3, 17-diol] an estrogen (Figure 3).
Figure 3. Structural Formulas
TWIRLA is designed to provide daily exposure of 120 mcg LNG and 30 mcg EE. TWIRLA is a matrix type TDS consisting of a 15 cm2 active adhesive laminate center, surrounded by a peripheral inactive adhesive laminate. The entire area of TWIRLA is 28 cm2.
TWIRLA consists of 5 layers and a release liner which is removed and discarded prior to application. The two innermost layers contain the active ingredients (LNG and EE), as well as inactive components. Proceeding from the outer surface toward the surface adhering to the skin, the layers are (1) a woven peripheral backing layer, which is etched with “TWIRLA Levonorgestrel 120 mcg/day Ethinyl Estradiol 30 mcg/day”; (2) an inactive peripheral acrylic adhesive layer; (3) an inactive peripheral polyisobutylene adhesive layer; (4) an internal membrane to separate the active adhesive matrix from the inactive adhesive laminate; (5) the active adhesive matrix (Figure 4).
Figure 4. Schematic Depiction of the TWIRLA TDS
The inactive components are acrylic adhesives, capric acid, copovidone, crospovidone, dimethyl sulfoxide, ethyl lactate, lauryl lactate, polybutene, polyester internal membrane, polyester release liner, polyisobutylene adhesives, and woven polyester backing membrane. TWIRLA is not made with latex.
Combination hormonal contraceptives lower the risk of becoming pregnant primarily by suppressing ovulation.
TWIRLA exhibited ovulation inhibition as defined by serum progesterone concentrations. In one study subjects were treated with TWIRLA for three cycles. In this study, approximately 80% of these subjects had serum progesterone concentrations < 4.7 ng/mL.
TWIRLA is a TDS designed with an active matrix core containing LNG and EE. TWIRLA delivers medication to the systemic circulation by absorption of LNG and EE through the skin.
Absorption
Following application of TWIRLA, both LNG and EE reach a plateau by 24 to 48 hours (Figures 5 and 6). Delivery of hormones is continuous over the 7 days of TWIRLA wear. The mean pharmacokinetic parameters (Css and AUC0‑168) for LNG and EE following two consecutive cycles of TWIRLA are summarized in Table 6.
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NC: not calculable |
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Analyte | Parameter | Cycle 1
Week 1 (N=18) | Cycle 1
Week 3 (N=18) | Cycle 2
Week 1 (N=18) | Cycle 2
Week 3 (N=18) |
LNG | Css (pg/mL)† | 842 (41.2) | 2009 (47.2) | 1389 (46.5) | 2209 (44.5) |
AUC0-168
(ng∙h/mL)‡ | 120.0 (39.1) | 339.0 (41.1) | 207.0 (44.1) | 378.0 (43.8) | |
t1/2 (h)§ | NC | 38.2 (22.7) | NC | 40.5 (15.4) | |
EE | Css (pg/mL)† | 31.9 (37.4) | 34.8 (37.4) | 38.6 (41.7) | 40.3 (38.9) |
AUC0-168
(pg∙h/mL)‡ | 5040 (35.4) | 6210 (34.2) | 6060 (35.9) | 7120 (36.6) | |
t1/2 (h)§ | NC | 19.7 (18.8) | NC | 20.5 (18.2) |
In multiple dose studies, AUC0-168 for LNG and EE showed within-cycle and between cycle increases and the mean serum concentrations of EE and LNG were highest during the third Week of Cycle 2 after two consecutive cycles of wear (Figures 5 and 6). In a three-cycle study, the steady-state pharmacokinetics of EE and LNG was reached during Cycle 2. Upon removal of TWIRLA, serum levels of EE and LNG reach non‑measurable levels and low levels within 3 days, respectively.
Figure 5. Mean Serum Ethinyl Estradiol Concentrations in Healthy Female Volunteers Following Two Consecutive Cycles of TWIRLA Wear on the Buttock (Vertical arrow indicates time of TWIRLA removal)
Figure 6. Mean Serum Levonorgestrel Concentrations in Healthy Female Volunteers Following Two Consecutive Cycles of TWIRLA Wear on the Buttock (Vertical arrow indicates time of TWIRLA removal)
The absorption of LNG and EE following application of TWIRLA to the buttock, abdomen, and upper torso (excluding the breasts) was examined. While absorption from the abdomen was slightly lower than from other sites, absorption from all three anatomic sites was considered to be therapeutically equivalent.
The absorption of LNG and EE following application of TWIRLA was studied under various external conditions including sauna, whirlpool, treadmill, and in a cold-water bath. Somewhat lower drug concentration levels were reported for whirlpool and treadmill with geometric ratios within the 78-90% range for both LNG and EE and dry sauna (LNG only).
Distribution
LNG in serum is primarily bound to sex hormone-binding globulin (SHBG). EE is about 97% bound to plasma albumin. EE does not bind to SHBG but induces SHBG synthesis.
Elimination
Metabolism
Since TWIRLA is applied transdermally, first-pass metabolism (via the gastrointestinal tract and/or liver) of LNG and EE that would be expected with oral administration does not occur. Hepatic metabolism of LNG and EE occurs as described below.
Levonorgestrel: The most important metabolic pathways are reduction of the Δ4-3-oxo group and hydroxylation at positions 2α, 1β, and 16β, followed by conjugation. Most of the circulating metabolites are sulfates of 3α, 5β-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent LNG 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 LNG 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 CYP3A4 vary widely among individuals and can explain the variation in rates of EE 2-hydroxylation.
Excretion
LNG and its metabolites are excreted in the urine (40% to 68%) and in feces (16% to 48%). The mean terminal elimination half-life for LNG in TWIRLA is approximately 41 ± 6.2 hours at steady state.
EE is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic recirculation. The terminal elimination half-life of EE in TWIRLA is approximately 21 ± 3.7 hours at steady state.
The efficacy of TWIRLA was evaluated in one open label, single arm, multicenter trial in the United States (Study 1) (NCT02158572) of one-year duration that enrolled 2,031 women, ranging in age between 18 and 60 years, who were healthy and sexually active with regular menstrual cycles. For the primary efficacy analysis, 1,736 women between the ages 18 and 35 years completed 15,165 evaluable 28-day cycles with TWIRLA, where no back-up contraception was used, and sexual intercourse occurred.
The racial/ethnic distribution for the primary analysis was White (67%), Black/African American (24%), Asian (4%), American Indian/Alaskan Native (0.5%), Native Hawaiian/Pacific Islander (0.5%), Other/Multiple races (5%); 19% of the study population were Hispanic. The mean age was 26 years.
The mean BMI in the primary efficacy analysis group was 28.3 kg/m2, and 35.3% of subjects had a BMI 30 kg/m2. The primary efficacy endpoint was the Pearl Index (PI) defined as the pregnancy rate per 100 woman-years of use. The overall PI for the primary analysis population (TWIRLA-treated patients) was 5.8 (95% CI 4.5, 7.2). There were clear differences in efficacy by BMI category as shown in Table 7 below.
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BMI | Number of evaluable cycles | Pearl Index (95% CI) |
< 25 kg/m2 | 6007 | 3.5 (1.8 - 5.2) |
≥ 25 and < 30 kg/m2 | 3881 | 5.7 (3.0 - 8.4) |
≥ 30 kg/m2 | 5264 | 8.6 (5.8 - 11.5) |
Figure 7 shows a model of the rate of pregnancy as BMI increases based on data from Study 1. There is an increase in pregnancy rate (i.e., the number of pregnancies per 100 woman-years), as BMI increased based on the primary analysis population (N = 1,735). TWIRLA is contraindicated in women with a BMI ≥ 30 kg/m2 [see Indications and Usage (1) and Contraindications (4)].
Figure 7. Pregnancy Rates (Estimated*) in TWIRLA-Treated Patients as BMI Increases for Women ≤ 35 Years of Age in Study 1
*Plot is based on Poisson Model with continuous BMI as the predictor (N=1,735); one woman in the primary analysis population had no BMI information. The solid line displays the estimated pregnancy rate, and the shaded area displays the 95% confidence interval for the estimated pregnancy rate.
Adhesion
Based on a Phase 1 study in 78 subjects wearing one TWIRLA on the lower abdomen for 7 days, 77 systems applied (98.7%) exhibited 75% or greater surface area adhesion at all timepoints evaluated (every 24 hours) throughout the wear period. In the Phase 3 trial, 5.0% of all transdermal systems worn during the year-long trial (55,900 transdermal systems) fully detached. Subject-reported adhesion was generally better for the abdomen as compared to the upper torso and buttock. Full detachment rates were higher for transdermal systems exposed to water as compared to transdermal systems with no water exposure.
TWIRLA (levonorgestrel and ethinyl estradiol) transdermal system is a beige 28 cm2 round product etched with “TWIRLA Levonorgestrel 120 mcg/day Ethinyl Estradiol 30 mcg/day” and supplied as:
Store at room temperature 20°C to 25°C (68°F to 77°F) with excursions permitted 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Store in original unopened pouch.
Used TDS still contain some active hormones. To discard, fold the sticky sides of the TDS together, place in a sturdy container, preferably with a child-resistant cap, and place this container in the trash. Used TDS should not be flushed down the toilet. See www.fda.gov/drugdisposal for more information about disposal of medicines.
Advise the woman to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Cigarette Smoking
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 (5.1)].
Venous Thromboembolism
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 CHC.
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 (4)].
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 patch (left your patch on more than 7 days)?” and “What if you forget to remove your patch for the patch free week?” in the FDA-approved patient labeling (Instructions for Use) [see Dosage and Administration (2.3)].
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 (2.1)].
A back-up or alternative method of contraception is needed when enzyme inducers are used with TWIRLA [see Drug Interactions (7.1)].
Lactation
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 breast-feeding [see Use in Specific Populations (8.2)].
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 (5.9)].
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.
PATIENT INFORMATION |
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What is the most important information I should know about TWIRLA?
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Hormonal birth control methods help to lower the chances of becoming pregnant when taken as directed. TWIRLA does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs). |
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What is TWIRLA? TWIRLA is:
TWIRLA is less effective in women with a BMI of 25 kg/m2 or more. |
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How well does TWIRLA work? Your chance of getting pregnant depends on how well you follow the directions for using TWIRLA. The better you follow the directions, the less chance you have of getting pregnant.
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Do not use TWIRLA if you:
TWIRLA may not be a good choice for you if you have ever had jaundice (yellowing of the skin or eyes) caused by pregnancy (also called cholestasis of pregnancy) or related to previous use of hormonal birth control.
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Before using TWIRLA, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines and herbal products may make TWIRLA less effective or cause breakthrough bleeding, including, but not limited to:
Ask your healthcare provider if you are not sure if you take any of the medicines listed above.
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How should I use TWIRLA?
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What should I avoid while using TWIRLA?
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What are the possible side effects of TWIRLA? TWIRLA may cause serious side effects, including:
It is possible to die or be permanently disabled from a problem caused by a blood clot, such as a heart attack or a stroke. Some examples of serious blood clots are blood clots in the: |
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Likelihood of Developing a Serious Blood Clot (Venous Thromboembolism [VTE]) *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 nine months, the rate is 7 to 27 per 10,000 Woman Years (WY). |
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Call your healthcare provider right away if you have: ο leg pain that does not go away ο sudden shortness of breath
The most common side effects of TWIRLA include: |
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These are not all the possible side effects of TWIRLA.
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How should I store TWIRLA?
Keep TWIRLA and all medicines out of the reach of children. |
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General information about the safe and effective use of TWIRLA. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use TWIRLA for a condition for which it was not prescribed. Do not give TWIRLA to other people. It may harm them. You can ask your pharmacist or healthcare provider for information about TWIRLA that is written for health professionals. |
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Does hormonal birth control cause cancer? It is not known if hormonal birth control causes breast cancer. Some studies, but not all, suggest that there could be a slight increase in the risk of breast cancer among current users with longer duration of use.
When you use TWIRLA you may have bleeding and spotting between periods, called unplanned bleeding. Unplanned bleeding may vary from light slight staining between menstrual periods to breakthrough bleeding which is a flow much like a regular period. Unplanned bleeding occurs most often during the first few months of hormonal contraceptive use but may also occur after you have been using the patch for some time. Such bleeding may be temporary and usually does not indicate any serious problems. It is important to continue using the patch on schedule. If the unplanned bleeding or spotting occurs in more cycles, is unusually heavy, or lasts for more than a few days, talk to your healthcare provider.
You should consider the possibility that you are pregnant if you miss your scheduled period. Because scheduled periods may not happen as often when you are using TWIRLA, tell your healthcare provider that you have missed your period and that you are using TWIRLA. Also, notify your healthcare provider if you have symptoms of pregnancy such as morning sickness or unusual breast tenderness. It is important that your healthcare provider checks to see if you are pregnant. Stop using TWIRLA if you are pregnant.
You may stop using TWIRLA whenever you wish. Consider a visit with your healthcare provider for a pre-pregnancy check-up before you stop using TWIRLA. |
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What are the ingredients in TWIRLA? Active ingredients: levonorgestrel (a progestin) and ethinyl estradiol (an estrogen) Inactive ingredients: polyester release liner, woven polyester backing membrane, acrylic adhesives, polyester internal membrane, polyisobutylene adhesives, copovidone, polybutene, crospovidone, lauryl lactate, dimethyl sulfoxide, capric acid, and ethyl lactate. |
INSTRUCTIONS FOR USE TWIRLA® (TWER-la) (levonorgestrel and ethinyl estradiol) transdermal system |
TWIRLA is for skin use only.
Read this Instructions for Use before you start using the TWIRLA transdermal system (TDS) (also called a patch) and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your contraceptive treatment.
Do not cut, damage or change the TWIRLA patch in any way. If the patch is cut, damaged or changed in any way, it may be less effective.
Starting TWIRLA for the first time: If you are starting TWIRLA for the first time, you should wait until you begin your menstrual period.
If you are changing from the oral hormone birth control pills, vaginal contraceptive ring or another transdermal patch to TWIRLA:
If you are starting TWIRLA after a miscarriage or abortion:
If you are starting TWIRLA after childbirth:
How to Apply TWIRLA:
Where should the patch be applied?
Where not to place the patch.
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Step 1. Tear the pouch open at the notch on the pouch. |
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Step 2. Open the pouch and carefully remove the patch. The patch is attached to a clear protective liner. |
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Avoid touching the sticky side of the patch |
Step 3a. Hold the patch with the clear protective liner facing you. You will see two sections: a large section and a small section.
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Step 4. Hold the small section of the liner and apply the sticky side of the patch to the chosen patch site. |
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Step 5. Press the sticky side of the patch firmly onto your skin and smooth it down. |
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Avoid wrinkles or folds | ||
Step 6. If the patch is not flat on the skin or there are large wrinkles, gently pull the patch off the skin while holding only the remaining protective liner and then put it on again. | ||
Step 7. After the patch is flat with no wrinkles, pull an edge of the remaining protective liner and gently pull it off. |
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Step 8a. After the patch is on your body, press the entire patch firmly into place with your hand for 10 seconds, making sure the edges stick well.
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Step 9. The edges of the patch should be smoothed over with your finger and make sure there is good contact around the patch with your skin and make sure there are no wrinkles. |
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Step 10. It is important that you check the patch every day to make sure it is in the right place. The patch should be checked after any water exposure (such as bathing, showering, or swimming) to make sure it is in the right place because water may affect how well the patch sticks to your skin. |
How do I throw away TWIRLA patches?
When should I change the TWIRLA patch?
What if a patch starts to lift off your skin or completely comes off?
Can I wear the patch when I am exercising, or using a sauna, swimming pool, or whirlpool?
What if you forget to change your patch (left your patch on more than 7 days)?
Frequent Patch Situations |
Will I have a |
Will I need to start a New 4 week Patch Cycle |
Will I need a backup Birth Control method |
Did not apply patch on scheduled Day 1 of new patch cycle |
Yes |
Yes |
Yes (for 7 days) |
Patch not attached for less than 24 hours |
No |
No |
No |
Patch not attached for 24 hours or more, or unsure how long |
Yes |
Yes |
Yes (for 7 days) |
Less than 48 hours late for Patch Change Day (Day 8 or 15) |
No |
No |
No |
48 hours or more late for Patch Change Day (Day 8 or 15) |
Yes |
Yes |
Yes (for 7 days) |
Forgets to remove last patch on Day 22 |
No |
No |
No |
What if you forget to remove your patch for the patch free week?
What if you wish to change your Patch Change Day?
Your TWIRLA patch should never be off more than 7 days in a row.
Manufactured by:
Corium International, Inc.
4558 50th Street, SE
Grand Rapids, MI 49512
Manufactured for:
Agile Therapeutics, Inc.
500 College Rd. E, Suite 310
Princeton, NJ 08540
For more information call 1-855-389-4752 or email: medicalaffairs@agiletherapeutics.com.
This Instructions for Use has been approved by the U.S. Food and Drug Administration |
Approved: 04/2022 |
TwirlaTM
(levonorgestrel and ethinyl estradiol)
transdermal system
120 mcg/day levonogestrel and 30 mcg/day ethinyl estradiol
Contains 1
transdermal
system
NDC: 71671-100-11
Each 28 cm2 system contains 2.6 mg levonorgestrel (LNG) and 2.3 mg ethyinyl estradiol
(EE). The inactive components are acrylic adhesives, capric acid, copovidone,
crospovidone, dimethyl sulfoxide, ethyl lactate, lauryl lactate, polyester backing,
polyester release liner, polyisobutylene adhesive, and woven polyester fabric.
This product is intended to prevent pregnancy. It does not protect against HIV
(AIDS) and other sexually trasmitted diseases.
Rx only. For Transdermal Use Only.
Keep out of reach of children. Package not child resistant.
Store at room temperature 20°C to 25°C (68°F to 77°F) with excursions permitted
to 15°C to 30°C (59°F to 86°F).
Recommended Dosage: See prescribing information. Apply immediately upon removal
from pouch. Each transdermal system is intended to be worn for 7 days - Fold used
system and discard prior to applying new system.
Mfd. For: Agile Therapeutics, Inc.
Princeton, NJ 08540
Mfd. By: Corium, Inc.
Grand Rapids, MI 49512
CAW1011
NDC: 71671-100-03
TwirlaTM
(levonorgestrel and ethinyl estradiol)
transdermal system
120 mcg/day levonogestrel and 30 mcg/day ethinyl estradiol
Contents: 3 transdermal systems
Each 28 cm2 system contains 2.6 mg levonorgestrel (LNG) and 2.3 mg
ethyinyl estradiol (EE). The inactive components are acrylic adhesives, capric
acid, copovidone, crospovidone, dimethyl sulfoxide, ethyl lactate, lauryl
lactate, polyester backing, polyester release liner, polyisobutylene adhesive,
and woven polyester fabric.
This product is intended to prevent pregnancy. It does not protect against
HIV (AIDS) and other sexually trasmitted diseases.
Rx only. For Transdermal Use Only.
Agile® THERAPEUTICS
REPLACEMENR
ONLY-
UP TO 1 WEEK
THERAPY
NDC: 71671-100-01
TwirlaTM
(levonorgestrel and ethinyl estradiol)
transdermal system
120 mcg/day levonogestrel and 30 mcg/day ethinyl estradiol
Contents: 1 replacement transdermal system
Each 28 cm2 system contains 2.6 mg levonorgestrel (LNG) and 2.3 mg
ethyinyl estradiol (EE). The inactive components are acrylic adhesives, capric
acid, copovidone, crospovidone, dimethyl sulfoxide, ethyl lactate, lauryl
lactate, polyester backing, polyester release liner, polyisobutylene adhesive,
and woven polyester fabric.
This product is intended to prevent pregnancy. It does not protect against
HIV (AIDS) and other sexually trasmitted diseases.
Rx only. For Transdermal Use Only.
Agile® THERAPEUTICS
TWIRLA
levonorgestrel/ethinyl estradiol patch |
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Labeler - Agile Therapeutics, Inc. (102678187) |
Mark Image Registration | Serial | Company Trademark Application Date |
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TWIRLA 87368536 not registered Live/Pending |
Agile Therapeutics, Inc. 2017-03-13 |
TWIRLA 85966257 4664449 Live/Registered |
TwistDx Limited 2013-06-21 |
TWIRLA 85507727 4601852 Live/Registered |
Agile Therapeutics, Inc. 2012-01-03 |