Twirla（炔雌醇和左炔诺孕酮）透皮系统

公司：Agile Therapeutics，Inc.

批准日期：2020年2月14日

治疗：避孕

Twirla（乙炔雌二醇和左炔诺孕酮透皮系统）是一种低剂量的激素避孕药，用于避孕。

2020年2月14日，新泽西州普林斯顿（GLOBE NEWSWIRE）-具有前瞻性的女性医疗保健公司Agile Therapeutics，Inc.（纳斯达克股票代码：AGRX）（Agile或Company）今天宣布，美国食品药品监督管理局（FDA）已批准Twirla（左炔诺孕酮和炔雌醇）透皮系统。

适应症和用途

Twirla被指示为BMI <30 kg / m2的具有生殖潜力的妇女的避孕方法，适合联合激素避孕的妇女。

使用限制

考虑在处方前Twirla对于BMI> 25至<30 kg / m2的女性有效性下降。 Bw> 30 kg / m2的女性禁用Twirla。

请参阅以下有关特威拉的重要安全信息，包括有关BMI> 30 kg / m2的女性吸烟和严重心血管事件及禁忌症的盒装警告。

“ Twirla是现有荷尔蒙避孕方法的重要补充，使开处方者现在可以向适当的美国女性提供每周一次的经皮选择，可提供与许多常用处方口服避孕药的标示剂量相符的雌激素水平，”主要研究者David Portman博士说。在SECURE临床试验中。 “我很高兴敏捷在不同的人群中进行了全面的研究，为开药者和寻求避孕的妇女提供了重要的数据。扩展所有避孕方法并告知适合个人计划生育需求和生活方式的选择至关重要。我很高兴医疗保健提供者现在可以将Twirla纳入可用的避孕选择之中。”

Twirla设计用于每周一次，可提供每天30 mcg的乙炔雌二醇（一种雌激素）和每天120 mcg的左炔诺孕酮（一种在该领域历史悠久的著名孕激素）。新批准的贴片可以戴在腹部，臀部或上躯干（不包括乳房）上。

“ FDA对Twirla的批准将使我们能够实现在避孕药具市场中建立敏捷的短期目标，并朝着我们的长期使命迈进，以扩大妇女的健康产品范围，包括在未满足需求的领域。我们对临床试验的患者，研究人员，医疗保健提供者和倡导者表示感谢，他们的贡献帮助我们获得了一种新的经皮避孕方法的批准，该方案可以满足许多女性的避孕需求和喜好。”董事长兼首席执行官Al Altomari说敏捷疗法执行官。 “我们为提供这一新选择感到自豪，并期待将Twirla带给妇女及其医疗保健提供者。”

作为Twirla批准的一部分，FDA要求Agile进行长期的前瞻性，观察性的上市后研究，以比较Twirla的新用户与其他联合使用的新用户的静脉血栓栓塞（VTE）和动脉血栓栓塞（ATE）风险。激素避孕药（CHC）。 FDA对Twirla的要求类似于最近批准的CHC的另一项上市后研究要求。 Twirla研究的最终研究报告定于2032年11月提交给FDA，临时安全数据应于2026年11月报告给FDA。敏捷还同意进行上市后承诺（PMC）研究，以评估产品的安全性。至少25名女性中残留的Twirla药物含量和强度，这将在规定的磨损后分析Twirla的炔雌醇和左炔诺孕酮的含量，并监测粘附性。 PMC与FDA在2019年11月发布的指南草案中要求贴剂开发人员进行的残留药物研究类似，该草案标题为“透皮和局部给药系统–产品开发和质量注意事项”。公司计划在2020年上半年开始设计批准后研究并评估相关成本。

在Twirla的批准下，敏捷将加快其商业活动。敏捷计划在2020年第一季度与托管医疗和患者付款人开展合作，以获取Twirla的市场准入。从2020年第二季度开始，公司计划雇用和培训初始销售团队。在开展这些活动的同时，Agile计划完成其商业制造过程的验证，并有望在2020年第四季度将初始产品运送给批发商。公司相信BMI <30 kg / m2的潜在新CHC用户代表了大量妇女。根据公司的市场研究，对当前和未来预期的美国避孕药市场的分析，以及对该类别其他产品的发布情况的回顾，公司估计Twirla可能会达到5-8％的峰值市场份额。在公司为Twirla的商业化做准备时，它将继续分析避孕药具市场并在评估Twirla的商业机会时更新其市场研究。

关于特威拉

重要安全信息

警告：BMI≥30 KG / M2的女性吸烟，严重心血管事件和禁忌

吸烟和严重心血管事件

吸烟会增加激素避孕药（CHC）的使用而导致发生严重心血管事件的风险。这种风险随着年龄的增长而增加，尤其是在35岁以上的女性中，并且随着吸烟数量的增加而增加。由于这个原因，包括TWIRLA在内的CHC在35岁以上吸烟的女性中是禁忌的。

BMI≥30 kg / m2的女性禁忌

Bw≥30 kg / m2的女性禁用Twirla。与BMI较低的女性相比，BMI≥30 kg / m2的女性有效性降低，可能发生静脉血栓栓塞事件（VTE）的风险更高。

禁忌症

Twirla是禁忌的，不宜用于动脉或静脉血栓形成疾病高风险的女性，包括BMI≥30 kg / m2的女性；具有局部神经系统症状的头痛，偏头痛伴有先兆偏头痛，35岁以上偏头痛的女性；肝肿瘤，急性病毒性肝炎或严重（代偿性）肝硬化或肝病；未确诊的子宫异常出血；怀孕;乳腺癌或其他对雌激素或孕激素敏感的癌症的当前或历史；对Twirla的任何成分过敏;含ombitasvir / paraparesis / ritonavir的丙型肝炎药物组合的使用以及有或没有达沙布韦的使用。

警告和注意事项

血栓栓塞性疾病和其他血管疾病

使用Twirla时，女性发生静脉血栓栓塞事件（VTE）的风险增加。

•如果发生动脉或静脉血栓形成/血栓栓塞事件，请停止Twirla

•如果出现无法解释的视力丧失，眼球突出，复视，乳头水肿或视网膜血管病变，请停止Twirla。立即评估视网膜静脉血栓形成

•在长时间固定期间停止Twirla，如果可行，在大手术之前和之后至少2周停止Twirla

•对于非母乳喂养的妇女，分娩后不早于四周开始服用Twirla

•开始Twirla之前，请评估过去的任何血栓栓塞或血栓栓塞病史或家族病史，并考虑病史是否提示遗传性或后天性高凝病

动脉事件-CHC会增加发生心血管事件和脑血管事件（如心肌梗塞和中风）的风险，尤其是在老年妇女（> 35岁），吸烟者和患有高血压，血脂异常，糖尿病或肥胖症的妇女中。

肝病-如果黄疸发生，请中止Twirla

伴随丙型肝炎治疗的肝酶升高的风险-在开始使用组合药物方案ombitasvir / paritaprevir / ritonavir联合或不联合dasabuvir进行治疗之前，停用Twirla。 Twirla可以在完成丙型肝炎联合药物治疗后约2周重新开始。

高血压-例行就诊时监测血压，如果血压明显升高则停止Twirla。据报道，使用CHC的女性血压升高，而使用时间延长的老年女性更可能出现这种血压升高。

胆囊疾病-研究表明CHC会增加患胆囊疾病的风险，也可能使现有的胆囊疾病恶化。

不利的碳水化合物和脂质代谢作用

•Twirla可能会降低葡萄糖耐量。仔细监测使用Twirla的糖尿病前期和糖尿病妇女。

•考虑对血脂异常不受控制的妇女采取替代避孕措施。 Twirla可能引起不利的脂质变化。高甘油三酸酯血症或其家族病史的女性在使用Twirla时血清甘油三酸酯浓度可能增加，这可能会增加胰腺炎的风险。

头痛-如果使用Twirla的妇女患上反复发作，持续性或严重的新头痛，请评估病因并在有指征时停用Twirla。如果在CHC使用过程中偏头痛的发生频率或严重性增加（可能是脑血管事件的前兆），请考虑停用Twirla。

出血不规则和闭经-使用Twirla的妇女可能会出现计划外的出血，尤其是在使用的头三个月内，或者没有计划的出血。如果出血持续存在或在先前的定期抽搐后在Twirla上发生，或者如果未发生计划的出血，则评估诸如怀孕的原因，或在计划外出血的情况下评估恶性程度。

其他警告和注意事项-其他警告和注意事项包括抑郁症，宫颈癌，结合球蛋白的血清浓度升高，遗传性血管性水肿和黄褐斑。

不良反应

在接受Twirla的女性中，有不到1％发生以下严重不良反应：胆石症，胆囊炎，重度抑郁，自杀意念，阑尾炎，异位妊娠，肺炎和肠胃炎。在3期临床试验中，在经Twirla治疗的患者中总共发现了4种VTE。在TWIRLA的临床试验中，最常见的不良反应（≥2％）是应用部位疾病，恶心，头痛，痛经和体重增加。

应建议患者Twirla不能预防HIV感染（AIDS）和其他性传播感染（STIs）。

药物相互作用

诱导某些酶（包括CYP3A4）的药物或草药产品可能会降低Twirla的有效性或增加突破性出血。当将酶诱导剂与Twirla一起使用时，建议患者使用备用或其他避孕方法。

适应症和用途

Twirla被指示为BMI <30 kg / m2的具有生殖潜力的妇女的避孕方法，适合联合激素避孕的妇女。

使用限制：

考虑在处方Twirla之前，Twirla对BMI≥25至<30 kg / m2的女性的有效性降低。 Bw≥30 kg / m2的女性禁用Twirla。

这不是与Twirla相关的安全信息的完整列表。

请参阅完整的处方信息，包括带框警告。

关于敏捷疗法公司

敏捷疗法公司是一家具有前瞻性的女性保健公司，致力于满足当今女性未满足的健康需求。 Twirla和我们的候选产品旨在为妇女提供避孕选择，使他们无需每天服用药丸，而无需使用更长效的方法。 Twirla®和我们的管道产品基于我们专有的透皮贴剂技术，即Skinfusion®，该技术旨在使药物通过皮肤输送。 有关更多信息，请访问公司网站www.agiletherapeutics.com。 公司有时可能会在公司网站上发布重大的非公开信息。

Company: Agile Therapeutics, Inc.
Date of Approval: February 14, 2020
Treatment for: Contraception

Twirla (ethinyl estradiol and levonorgestrel transdermal system) is a low-dose combined hormonal contraceptive patch for birth control.

PRINCETON, N.J., Feb. 14, 2020 (GLOBE NEWSWIRE) -- Agile Therapeutics, Inc., (Nasdaq: AGRX) (Agile or the Company), a forward-thinking women’s healthcare company, today announced that the U.S. Food and Drug Administration (FDA) has approved Twirla (levonorgestrel and ethinyl estradiol) transdermal system.

INDICATION AND USAGE

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.

Limitations of Use

Consider Twirla’s reduced effectiveness in women with a BMI > 25 to < 30 kg/m2 before prescribing. Twirla is contraindicated in women with a BMI > 30 kg/m2.

Please see Important Safety Information for Twirla, including BOXED WARNING on Cigarette Smoking and Serious Cardiovascular Events and Contraindication in Women with a BMI > 30 kg/m2, below in About Twirla.

“Twirla is an important addition to available hormonal contraceptive methods, allowing prescribers to now offer appropriate U.S. women a weekly transdermal option that delivers estrogen levels in line with labeled doses of many commonly prescribed oral contraceptives,” said Dr. David Portman, a primary investigator on the SECURE clinical trial. “I’m pleased that Agile conducted a comprehensive study in a diverse population providing important data to prescribers and to women seeking contraception.  It is vital to expand the full range of contraceptive methods and inform the choices that fit an individual’s family planning needs and lifestyle.  I am excited healthcare providers can now include Twirla among available contraception options.”

Twirla is designed for weekly application to deliver a 30 mcg daily dose of ethinyl estradiol, a type of estrogen, along with a 120 mcg daily dose of levonorgestrel, a well-known progestin with a long history in the category.  The newly approved patch can be worn on the abdomen, buttock, or upper torso (excluding the breasts).

“The FDA’s approval of Twirla will enable us to deliver on our short-term goal of establishing Agile in the contraceptive prescription market and working towards our longer-term mission to broaden our women’s health portfolio, including in areas of unmet need. We are grateful to the clinical trial patients, researchers, healthcare providers, and advocates, whose contributions helped us secure the approval of a new transdermal contraceptive option that may serve the contraceptive needs and preferences of many women,” said Al Altomari, chairman and chief executive officer, Agile Therapeutics. "We are proud to offer this new option and look forward to bringing Twirla to women and their healthcare providers.”

As part of Twirla’s approval, the FDA is requiring Agile to conduct a long-term prospective, observational post-marketing study comparing the risks for venous thromboembolism (VTE) and arterial thromboembolism (ATE) in new users of Twirla to new users of other combined hormonal contraceptives (CHC).  The FDA’s requirement for Twirla is similar to another post-marketing study requirement for a recently approved CHC.  The final study report for the Twirla study is scheduled to be submitted to the FDA in November 2032, with interim safety data reporting to the FDA due in November 2026.  Agile has also agreed to a post-marketing commitment (PMC) study to assess the residual drug content and strength of Twirla in a minimum of 25 women, which will analyze the Twirla ethinyl estradiol and levonorgestrel content after the prescribed wear and will monitor adhesion. The PMC is similar to residual drug studies requested of patch developers in the FDA’s November 2019 draft guidance entitled Transdermal and Topical Delivery Systems – Product Development and Quality Considerations.  The Company plans to begin designing the post-approval studies and evaluating related costs during the first half of 2020.

With the approval of Twirla, Agile will accelerate its commercial activities.  In the first quarter of 2020, Agile plans to initiate work with managed care and patient payors to gain market access for Twirla.  Beginning in the second quarter of 2020, the Company plans to hire and train an initial sales team. In parallel with these activities, Agile plans to complete the validation of its commercial manufacturing process and expects to ship initial product to wholesalers in the fourth quarter of 2020. The Company believes that the potential new CHC users who have a BMI <30 kg/m2 represent a significant population of women.  Based on the Company’s market research, analysis of the current and expected future U.S. contraceptive market, and review of other product launches in the category, the Company estimates that Twirla can potentially achieve a peak market share of 5-8%.  As the Company prepares for the commercialization of Twirla, it will continue to analyze the contraceptive market and update its market research as it evaluates the commercial opportunity for Twirla.

About Twirla

IMPORTANT SAFETY INFORMATION

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS and CONTRAINDICATED IN WOMEN WITH A BMI ≥ 30 KG/M2
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. 

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).

CONTRAINDICATIONS

Twirla is contraindicated and should not be used in women with a high risk of arterial or venous thrombotic disease, including women with a BMI ≥ 30 kg/m2; have headaches with focal neurological symptoms, migraine with aura, women over 35 years of age with any migraine headache; liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis, or liver disease; undiagnosed abnormal uterine bleeding; pregnancy; current or history of breast cancer or other estrogen- or progestin-sensitive cancer; hypersensitivity to any components of Twirla; and use of Hepatitis C drug combinations containing ombitasvir/paraparesis/ritonavir with or without dasabuvir.

WARNINGS AND PRECAUTIONS

Thromboembolic Disorders and Other Vascular Conditions-
Women are at increased risk for a venous thromboembolic event (VTE) when using Twirla.

· Stop Twirla if an arterial or venous thrombotic/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, if feasible, stop Twirla at least 4 weeks before and through 2 weeks after major surgery

· Start Twirla no earlier than four weeks after delivery in women who are not breast-feeding

· Before starting Twirla, evaluate any past medical history or family history of thromboembolism or thromboembolic disorders and consider whether history suggests inherited or acquired hypercoagulopathy

Arterial Events- CHCs increase the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke, particularly among older women (> 35 years of age), smokers, and women with hypertension, dyslipidemia, diabetes, or obesity.

Liver Disease- Discontinue Twirla if jaundice develops
 
Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment- 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.

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. 

Gallbladder Disease- Studies suggest CHCs increase risk of developing gallbladder disease and may also worsen existing gallbladder disease.
 
Adverse Carbohydrate and Lipid Metabolic Effects-

· 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.

Headache- 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- Women using Twirla may experience unscheduled bleeding, especially during the first three months of use, or experience absence of scheduled bleeding. If bleeding persists or occurs after previously regular cycles on Twirla, or if scheduled bleeding does not occur, evaluate for causes such as pregnancy or, in the case of unscheduled bleeding, malignancy.

Other Warnings and Precautions- Other warnings and precautions include, depression, cervical cancer, increased serum concentrations of binding globulins, hereditary angioedema, and chloasma.
 
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. A total of four VTEs in Twirla-treated patients were identified in the Phase 3 clinical trial. The most common adverse reactions (≥2%) in clinical trials for TWIRLA are application site disorders, nausea, headache, dysmenorrhea, and increased weight.
Patients should be counseled that Twirla does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs).

DRUG INTERACTIONS
Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of Twirla or increase breakthrough bleeding.  Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with Twirla.

INDICATIONS AND USAGE
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.
Limitations of Use:
Consider Twirla’s reduced effectiveness in women with a BMI ≥ 25 to < 30 kg/m2 before prescribing Twirla. Twirla is contraindicated in women with a BMI ≥ 30 kg/m2.

This is not a comprehensive list of safety information related to Twirla. 
Please See Full Prescribing Information, including BOXED WARNING.

To report SUSPECTED ADVERSE REACTIONS, call 1-855-888-2467 or report via the FDA MedWatch Program at www.fda.gov/medwatch or 1-800-FDA-1088.

About Agile Therapeutics, Inc.

Agile Therapeutics is a forward-thinking women's healthcare company dedicated to fulfilling the unmet health needs of today’s women.  Twirla and our product candidates are designed to provide women with contraceptive options that offer freedom from taking a daily pill, without committing to a longer-acting method.  Twirla® and our pipeline products are based on our proprietary transdermal patch technology, called Skinfusion®, which is designed to allow drug delivery through the skin. For more information, please visit the company website at  www.agiletherapeutics.com. The Company may occasionally disseminate material, nonpublic information on the Company’s website.

Forward-Looking Statement

Certain information contained in this press release includes “forward-looking statements”, within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, related to our regulatory submissions for Twirla. We may, in some cases use terms such as “predicts,” “believes,” “potential,” “continue,” “anticipates,” “estimates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “likely,” “will,” “should” or other words that convey uncertainty of the future events or outcomes to identify these forward-looking statements. Our forward-looking statements are based on current beliefs and expectations of our management team that involve risks, potential changes in circumstances, assumptions, and uncertainties, including statements regarding the market availability of Twirla.  Any or all of the forward-looking statements may turn out to be wrong or be affected by inaccurate assumptions we might make or by known or unknown risks and uncertainties. These forward-looking statements are subject to risks and uncertainties including risks related to our ability maintain regulatory approval of Twirla, our ability along with our third-party manufacturer, Corium, to complete successfully the scale-up of the commercial manufacturing process for Twirla, including the qualification and validation of equipment related to the expansion of Corium's manufacturing facility, the performance and financial condition of Corium or any of the suppliers to our third-party manufacturer, the ability of Corium to produce commercial supply in quantities and quality sufficient to satisfy market demand for Twirla, our ability to successfully commercialize Twirla, the successful development of our sales and marketing capabilities, the accuracy of our estimates of the potential market for Twirla, regulatory and legislative developments in the United States and foreign countries, our ability to obtain and maintain intellectual property protection for Twirla, our strategy, business plans and focus, and the other risks set forth in our filings with the U.S. Securities and Exchange Commission, including our Annual Report on Form 10-K and our Quarterly Reports on Form 10-Q.  For all these reasons, actual results and developments could be materially different from those expressed in or implied by our forward-looking statements. You are cautioned not to place undue reliance on these forward-looking statements, which are made only as of the date of this press release. We undertake no obligation to publicly update such forward-looking statements to reflect subsequent events or circumstances.

SOURCE:  Agile Therapeutics, Inc.

Posted: February 2020