Twirla Drug Information

TWIRLA is indicated as a method of contraception for use in women of reproductive potential with a BMI < 30 kg/m 2 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/m 2 before prescribing TWIRLA.

How to Start Using TWIRLA 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): Table 1: Instructions for Administration 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. 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.

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.

Important Application Instructions See the FDA-approved patient labeling ( Instructions for Use ). TWIRLA TDS is applied once weekly for three weeks. Each TWIRLA TDS should be worn for one week.

Instruct women to wear only one TWIRLA TDS at any time. To achieve maximum contraceptive effectiveness, TWIRLA must be used exactly as directed. The failure rate may increase when TDS application is delayed/missed or when TDS is applied incorrectly.

Apply TWIRLA to clean, dry, and intact skin at the selected application site. Application sites include: the abdomen, buttock or upper torso (excluding the breasts). When applying a new TWIRLA TDS, do not apply the new TDS directly over the previous TDS site.

Do not apply TWIRLA to skin that has been exposed to powder, oil, moisturizer, or lotion. Advise women not to routinely use large amounts of body lotions or oils at application sites. Prolonged exposure to water may interfere with adherence of TWIRLA.

Do not cut or alter TWIRLA in any way, the whole TDS should be applied. If the TWIRLA TDS is cut or damaged or altered in size, contraceptive efficacy may be impaired. If the TWIRLA TDS lifts at the edges, reattach TWIRLA by pressing firmly and smoothing down the edges of the system.

If TWIRLA comes off completely, reapply the TWIRLA TDS that detached. Discard TWIRLA by folding the used TDS so that the adhesive side sticks to itself and safely discard in the trash. 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: The woman should press down firmly on the TDS with the palm of the hand for 10 seconds, making sure that the whole TDS is adhered to her skin.

Then run fingers over the entire surface area to smooth out any wrinkles around the edges of the TDS. If the lifted edge of the TDS does not stick completely after attempted re-adhesion, the TDS should be removed, and a new replacement TDS applied. Do not tape or wrap the TDS to the skin or reapply a TDS that is partially adhered to clothing.

If the TDS has been off or partially off: For less than one day, the woman should try to reapply it. If the TDS does not adhere completely, apply a new TDS immediately. No back-up contraception is needed and the “Patch Change Day” will stay the same.

For more than one day OR if unsure of the timeframe, the woman may not be protected from pregnancy. To reduce this risk, apply a new TDS and start a new 4-week cycle. The woman will now have a new “Patch Change Day” and MUST USE NON-HORMONAL BACK-UP CONTRACEPTION (such as condoms and spermicide, or diaphragm and spermicide) for the first 7 days of the new cycle.

Missed Doses

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: At the start of any TDS cycle (Week 1/Day 1): THE WOMAN MAY NOT BE PROTECTED FROM PREGNANCY. The woman should apply the first TDS of her new cycle as soon as she remembers, and this becomes the new "Patch Change Day" and a new "Day 1" of the cycle.

The next TDS should be applied on the usual "Patch Change Day". No back-up contraception is needed. For more than 2 days (48 hours or more): THE WOMAN MAY NOT BE PROTECTED FROM PREGNANCY.

The woman should stop the current contraceptive cycle and start a new four-week cycle immediately by putting on a new TDS. This is now a new "Patch Change Day" and a new "Day 1" of the cycle. Non-hormonal back-up contraception must be used for 7 days.

At the end of the TDS cycle Week 3 (Day 22): If the woman forgets to remove her TDS, she should take it off as soon as she remembers. The next cycle should be started on the usual "Patch Change Day", which is the day after Day 28. Table 2: Managing Partial or Complete TDS Detachments and Late/Missed TDS Applications Under no circumstances should there be more than a seven-day TDS-free interval between cycles.

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.

Clinical Trial Experience

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. Women applied TWIRLA (40 mcg LNG/10 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/m 2. 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.

Table 3: Adverse Drug Reactions Reported by 2% of TWIRLA-Treated Women in One Phase 3 Clinical Trial *Represents a bundle of similar terms that include the following adverse reactions: application site acne, hemorrhage, pustules, dermatitis, hypersensitivity, rash, discoloration, induration, reaction, dryness, irritation, ulcer, erosion, pain, urticaria, erythema, papules, vesicles, exfoliation, pruritis. 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/m 2.

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.

Postmarketing Experience

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. image description

Effects of Other Drugs on Combined Hormonal Contraceptives 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. Table 4: Significant Drug Interactions Involving Substances That Affect CHCs Metabolic Enzyme Inducers Clinical effect Concomitant use of CHCs with metabolic enzyme inducers may decrease the plasma concentrations of the estrogen and/or progestin component of CHCs. Decreased exposure of the estrogen and/or progestin component of CHCs may potentially diminish the effectiveness of CHCs and may lead to contraceptive failure or an increase in breakthrough bleeding. significantly decreases systemic exposure of ethinyl estradiol.

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).

Effects of Combined Hormonal Contraceptives on Other Drugs Table 5 provides significant drug interaction information for drugs co-administered with TWIRLA. Table 5: Significant Drug Interaction Information for Drugs Co-Administered with CHCs Lamotrigine Clinical effect Concomitant use of CHCs with lamotrigine may significantly decrease systemic exposure of lamotrigine due to induction of lamotrigine glucuronidation. Prevention or management Dose adjustment may be necessary.

Thyroid Hormone Replacement Therapy or Corticosteroid Replacement Therapy Clinical effect Concomitant use of CHCs with thyroid hormone replacement therapy or corticosteroid replacement therapy may increase systemic exposure of thyroid-binding and cortisol-binding globulin. 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.

Other Drugs Clinical effect Concomitant use of CHCs may decrease systemic exposure of acetaminophen, morphine, salicylic acid, and temazepam. 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.

Effect on Laboratory Tests

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

Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation CHCs are contraindicated for use with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. 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.

Pregnancy 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.

Pediatric Use The safety and effectiveness of TWIRLA as a method of contraception have been established in females of reproductive potential with a BMI < 30 kg/m 2. Efficacy is expected to be the same in postmenarcheal females regardless of age. TWIRLA is not indicated in females before menarche.

Twirla is contraindicated in females who are known to have or develop the following conditions: At high risk of arterial or venous thrombotic diseases. Examples include women who Smoke, if over age 35 Have current or history of deep vein thrombosis or pulmonary embolism Have cerebrovascular disease Have coronary artery disease Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) Have inherited or acquired hypercoagulopathies Have uncontrolled hypertension or hypertension with vascular disease 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 Have headaches with focal neurological symptoms, migraine headaches with aura Women over age 35 with any migraine headaches BMI ≥ 30 kg/m 2. Compared to women with a lower BMI, women with a BMI ≥ 30 kg/m 2 had reduced effectiveness and may have a higher risk for VTEs.

Liver tumors (benign or malignant), acute viral hepatitis, or severe (decompensated) cirrhosis, or liver disease Undiagnosed abnormal uterine bleeding Pregnancy, given there is no reason to use CHCs during pregnancy Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive Hypersensitivity to any components of Twirla. Observed reactions include itching and irritation at the TDS application site Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for alanine aminotransferase (ALT) elevations High risk of arterial or venous thrombotic diseases Breast cancer BMI ≥ 30 kg/m 2 Liver tumors, acute viral hepatitis or decompensated cirrhosis Undiagnosed abnormal uterine bleeding Pregnancy Hypersensitivity reactions to components of Twirla Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir

There have been no reports of serious adverse outcomes from overdose of CHCs, including ingestion by children. Overdose may cause uterine bleeding in women and nausea. In case of suspected overdose, the TWIRLA TDS should be removed and symptomatic treatment given.