2010年5月6日，美国食品药品管理局(FDA)和拜耳制药公司(BayerHealthCarePharmaceuticals)宣布，避孕药Natazia(戊酸雌二醇和戊酸雌二醇/地诺孕素)片剂正式获批。美国加州托兰斯加州大学洛杉矶分校Harbor医学中心的妇产科教授AnitaNelson博士说：“每位女性对激素的机体反应都有所不同，因此有必要提供多种避孕选择。她们在与医务人员共同决定采用哪种避孕措施对其最为恰当时，Natazia应该是值得考虑的不错选择之一。”

FDA在新闻发布会上称，Natazia是首个在美国获准上市的四相口服避孕药。四相是指在每个为期28天的治疗周期内4次口服孕激素和雌激素的剂量各不相同。Natazia与之前上市的复方口服避孕药(COC)相比还有一点区别，即所含的雌激素成分为戊酸雌二醇，而非乙炔雌二醇。

在北美和欧洲开展的两项多中心3期临床试验对Natazia作为口服避孕药的安全性和有效性进行了评估。这两项试验共纳入1,867例女性，共观察了近30,000个为期28天的治疗周期。这两项试验均证实，Natazia作为一种激素类避孕药是有效的。

已观察到的Natazia的最常见不良反应包括：不规则出血、乳房触痛、头痛、恶心、呕吐、体重增加和痤疮。

对于动脉或静脉血栓形成性疾病、诊断不明的生殖器异常出血、乳腺癌或其他雌激素或孕激素敏感性癌症、肝脏肿瘤(良性或恶性)或肝脏疾病高危人群，应避免使用Natazia。使用Natazia可能导致出现多种严重疾病的风险增加，包括静脉和动脉血栓形成性和血栓栓塞性事件(包括心肌梗死、血栓栓塞和卒中)、肝脏肿瘤、胆囊疾病、高血压、卵巢囊肿破裂和子宫平滑肌瘤。在使用COC的第1年里，血栓栓塞性事件的风险增幅最高。

对于使用包括Natazia在内的COC产品的妇女，强烈建议其不要吸烟。吸烟会进一步增加因使用COC而引起的严重心血管不良反应的风险。年龄越大，吸烟量越大，风险就越高。尚未在体重指数>30kg/m2的女性中对Natazia开展过评价。

Bayer HealthCare

Pharmacological Class:
Oral contraceptive (progestin + estrogen)

Active Ingredient(s):
Estradiol valerate 3mg (2 tabs); dienogest 2mg + estradiol valerate 2mg (5 tabs); dienogest 3mg + estradiol valerate 2mg (17 tabs); estradiol valerate 1mg (2 tabs); inert (2 tabs).

Indication(s):
Oral contraception.

Pharmacology:
Natazia is a combined oral ­contraceptive (COC) that contains estradiol valerate as the estrogen and dienogest as the progestin. This type of contraceptive works primarily by suppressing ovulation and also by causing changes in cervical mucus and the endometrium, reducing the likelihood of implantation.

Estradiol valerate is converted by the liver to 17β-estradiol, which is further con­verted to estradiol, estrone, and other metab­olites. Dienogest is a progestin with some properties of 19-nortestosterone derivatives as well as those of progesterone derivatives.

Clinical Trials:
The safety and efficacy of Natazia was evaluated in two multicenter, open-label, single-arm clinical trials: one in North America involving 490 subjects 18–35 years of age treated for up to 28 cycles, and one in Europe involving 1377 subjects 18–50 years of age treated for 20 cycles.

The Pearl Index was the primary efficacy endpoint used to assess contraceptive reliability and was assessed in each of the two studies assuming all subjects were at risk of pregnancy in all medication cycles unless back-up con­traception was documented. The Pearl Index was based on pregnancies that occurred after the onset of treatment and within 7 days after the last pill intake. In the North American study, the Pearl Index was 1.64, and the con­traceptive failure rate was 0.016. For the ­European study in the 18–35 year age group, the Pearl Index was 1.04, and the contraceptive failure rate was 0.010.

Legal Classification:
Rx

Adults:
BMI >30kg/m2: insufficient data. 1 tab daily for 28 days; repeat. Use Day 1 start; use non-hormonal backup method for first 9 days. Do not skip doses or delay dose >12 hours. Switching from other methods: see literature.

Children:
Premenarchal: not applicable.

Contraindication(s):
High risk of arterial or venous thrombotic disease (eg, smokers or migraineurs over age 35, history of DVT or thrombo­embolism, cerebrovascular or coronary artery disease, thrombogenic valvular disease, atrial fibrillation, subacute bacterial endo­carditis, hypercoagulopathies, uncontrolled hyper­tension, diabetes with vascular disease, headaches with focal neurologic symptoms). Breast or other estrogen or progestin-sensitive neoplasms. Hepatic disease or tumors. Pregnancy (Cat.X).

Warnings/Precautions:
Discontinue if thrombotic event, unexplained visual changes, or jaundice occurs, and at least 4 weeks before through 2 weeks after surgery associated with increased risk of thromboembolism. Diabetes. Prediabetes. Depression. Uncontrolled dyslipidemias. Pregnancy-related cholestasis. Evaluate significant changes in headaches, irregular uterine bleeding, amenorrhea. Monitor blood pressure. Nursing mothers: not recommended.

Interaction(s):
May be antagonized by CYP3A4 or other enzyme inducers (eg, barbiturates, bos­entan, carbamazepine, felbamate, ­griseo­fulvin, oxcarbazepine, phenytoin, rifampin, St. John’s wort, topiramate) (use backup contraception). May be affected by protease inhibitors. May antagonize lamotrigine. May affect lab tests (eg, coag­u­lation factors, lipids, glucose tolerance, binding proteins). May need dose adjustment of thyroid hormones.

Adverse Reaction(s):
Headache, irregular uterine bleeding, mastodynia, GI upset, acne, increased weight; hypertension, transient delay of ovulation after discontinuation, edema, chloasma. Increased risk of gallbladder disease, thromboembolic disorders.

How Supplied:
Tabs—84 (3 packs)

Additional Patient Information:
Take at the same time daily, in the correct order. Missed pills, or if taken late by 12 hours or more, or if vomiting or diarrhea occurs within 4 hours after taking an active tablet, or concomitant interacting drug: use backup contraceptive measure (see literature).

首个治疗经血过多的口服避孕药获准

2012年3月14日，美国食品与药物管理局（FDA）批准了戊酸雌二醇和戊酸雌二醇/地诺孕素（Natazia， 拜耳医药保健公司生产）口服避孕药片用于治疗女性经血过多（HMB）。

根据该公司的公告，这个药是首个也是唯一适用于治疗HMB的口服避孕药。

当前的批准是根据2项纳入421名女性患者的多中心、随机、双盲安慰剂对照临床试验结果。这些女性患者年龄至少18岁，被诊断为功能失调性子宫出血，描述为大量出血、经期延长和或频繁出血，而无器质性病变。HMB定义为90天内至少发生两次经血量≥80ml的情况。患者被随机分为治疗组和安慰剂组，分别接受7个月经周期的治疗。在90天有效性评估期，两项研究治疗组的症状完全缓解率分别为29.2%和29.5%，而安慰剂组仅为2.9%和1.2%。

总之，与安慰剂组相比，治疗组HMB患者经血丢失明显减少（两项研究P值均<0 .0001）。

研究中至少2%的经治患者出现了最常见治疗相关性不良反应，包括头痛或偏头痛，乳房疼痛、不适或压痛，月经失调，恶心或呕吐，痤疮，情绪改变和体重增加。

尽管该药在2010年5月获准用于女性避孕，但Natazia用于避孕的有效性尚未在体质指数（BMI）大于30 kg/m 2的女性中确定。

http://berlex.bayerhealthcare.com/html/products/pi/natazia_pi.pdf