Twirla levonorgestrel/ethinyl estradiol 2.6 mg; 2.3 mg Patch, 3 patches

5 WARNINGS AND PRECAUTIONS Vascular Risks : Stop TWIRLA if a thromboembolic event occurs. Stop TWIRLA at least 4 weeks before and through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breast-feeding.

Consider cardiovascular risk factors before initiating in all women, particularly those over 35 years. ( 5.1 , 5.5 ) Liver Disease : Discontinue TWIRLA if jaundice occurs. ( 5.2 ) Risk of Liver Enzyme Elevations with Concomitant Hepatitis C .

( 5.3 ) Hypertension : If used in women with well-controlled hypertension, monitor blood pressure and stop use if blood pressure rises significantly. ( 5.4 ) Gallbladder Disease : May cause or worsen gallbladder disease. ( 5.6 ) Adverse Carbohydrate and Lipid Metabolic Effect : Monitor glucose in prediabetic and diabetic women using TWIRLA.

Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. ( 5.7 ) Headache : Evaluate significant change in headaches and discontinue TWIRLA if indicated. ( 5.8 ) Uterine Bleeding : May cause irregular bleeding or amenorrhea.

Evaluate for other causes if symptoms persist. ( 5.9 )

5.1Thromboembolic 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/m 2 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/m 2 [see Adverse Reactions ( 6.1 )] . 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 ( 4 )] . 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…

6 ADVERSE REACTIONS The following serious adverse reactions with the use of CHCs, including TWIRLA, are discussed elsewhere in the labeling: Thromboembolic Disorders and Other Vascular Conditions [see Warnings and Precautions ( 5.1 )] Liver disease [see Warnings and Precautions ( 5.3 )] 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 Exeltis USA, Inc. at 1-877-324-9349 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical 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 [see Clinical Studies ( 14 )] . 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 . The BMI of the safety population was widely distributed: 39.4% had a BMI < 25 kg/m 2 , 25.3% had a BMI ≥ 25 kg/m 2 and < 30 kg/m 2 , and 35.3% had a BMI ≥ 30 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 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% *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 [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.

6.2Postmarketing 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 studie…

7 DRUG INTERACTIONS 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. 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 )

7.1Effects 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 [see Clinical Pharmacology ( 12.3 )].

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. Prevention or management Counsel women to use an alternative method of contraception or a backup method when enzyme inducers are used with CHCs. Continue backup contraception for 28 days after discontinuing the enzyme inducer to maintain contraceptive reliability.

Examples Aprepitant, barbiturates, bosentan, carbamazepine, efavirenz, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, rifabutin, rufinamide, topiramate, products containing St. John’s wort, Induction potency of St. John’s wort may vary widely based on preparation. and certain protease inhibitors (see separate section on protease inhibitors below).

Colesevelam Clinical effect Concomitant use of CHCs with Colesevelam significantly decreases systemic exposure of ethinyl estradiol [see Clinical Pharmacology ( 12.3 )] . Decreased exposure of the estrogen component of CHCs may potentially reduce contraceptive efficacy or result in an increase in breakthrough bleeding, depending on the strength of ethinyl estradiol in the CHC. 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-administer…