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药品名称	通用名称：黄体酮阴道缓释凝胶 Progesterone Vaginal Slow Release gel  商品名称：雪诺同  Crinone
【 性状】	本品为白色或类白色乳状黏稠体。 本品预装于一次性白色聚乙烯给药器内。给药器专为阴道给药设计，顶端可拧断。
【 成份】	黄体酮  黄体酮的化学名称 ：孕甾-4烯-3，20-二酮，分子式 ：C21H30O2，分子量 ：314.47。 赋形剂 ：甘油、轻液状石蜡、氢化棕榈油甘油酯、卡波姆974P、山梨酸、聚卡波非、氢氧化钠和纯水。
【 功能主治】	用于辅助生育技术中黄体酮的补充治疗。
【 规格】	8％（90mg）
【 用法用量】	阴道给药，每天1次，1次90 mg（1支）。如果妊娠，持续治疗至胎盘具有自主功能为止，达到10-12周。 使用方法 1、从密封袋中取出给药器，此时请不要去除可拧断的盖帽。（在海拔2500英尺以上的地方使用时，请见下面的特别说明。） 2、用拇指与食指紧握给药器的粗端。用力甩3-4次（如体温计），确保将内含药物甩至给药器的细顶端。 3、紧握给药器的粗端的扁平部。拧下细顶端的盖帽，丢弃。当拧盖帽的时候请不要挤压粗端，因为这样可能会使凝胶在插入之前就被挤出来。 4、取坐姿或背卧姿势，弯曲膝盖，将给药器插入阴道。轻柔地将细端插入阴道。 5、按压给药器粗端，将凝胶挤到阴道内。取出给药器并将其丢弃在垃圾桶中。请不要担心残留在给药器中的一小部分凝胶，因为患者已经接受了正确和设定的剂量。 特别说明（在海拔2500英尺以上的地方使用时） 1、从密封袋中取出给药器，此时请不要去除可拧断的盖帽。如上所述，握紧给药器的粗端，用刺血针或插针式别针在粗端的扁平部刺一个小孔。这将会减小给药器由于高海拔地区而产生的内外压力差。这不会影响凝胶的给药量，因为患者将接受正确和设定的剂量。 2-4、步骤2-4同以上步骤2-4。 5、将拇指或食指放在给药器粗端的刺孔处。按压给药器粗端，将凝胶挤到阴道内。取出给药器并将其丢弃在垃圾桶中。请不要担心有一小部分凝胶遗留在给药器中，因为患者已经接受了正确和设定的剂量。 本药粘附在阴道内壁上、可长时间释放黄体酮。给药后数天，阴道分泌物中可能出现白色的微小球状物。这种现象很常见。 如果忘记了一次的剂量，在患者想起时应尽快使用，但是剂量不要超过推荐的日剂量。 本药不应该和其他阴道制剂同时使用。
【 药物过量】	如果用药过量，应停用本品，对患者应进行对症治疗以及相关支持的治疗措施。
【 禁忌】	已知对本品（黄体酮或任何其他成分）过敏 ；不明原因的阴道出血 ；肝功能障碍或肝脏疾病 ；已知或可能的乳腺或生殖器恶性肿瘤 ；急性卟啉症 ；血栓静脉炎、血栓栓塞性疾病、或有与激素有关的血栓静脉炎或血栓栓塞性疾病史、脑溢血或有相关病史的病人 ；稽留流产患者禁用。
【 注意事项】	医师应该留意出现血栓栓塞性疾病最早的症状（血栓静脉炎、脑血管疾病、肺栓塞和视网膜血栓形成）。一旦这些症状发生或可疑发生，应立即停止用药。 治疗前体检时应特别注意检查乳腺和盆腔器官，并进行宫颈脱落细胞涂片检查。 发生突破性出血和不规律阴道出血时，应考虑非功能性原因。发生不明原因的阴道出血时，应及时诊断并治疗。 由于黄体酮治疗可能会引起一定程度的体液潴留，应密切观察由此引起的疾病和症状（如癫痫、偏头痛、哮喘、心脏或肾功能不全）。 在提交相关样本时应告知病理医师关于黄体酮的治疗。 有精神抑郁症病史的患者使用本品治疗时应给予密切观察，如果严重抑郁症复发，应立即停药。 在使用雌激素-黄体酮联合用药的患者中，观察到有一小部分患者出现了葡萄糖耐量降低的现象。发生此现象的机制尚不清楚。因此，当糖尿病患者接受黄体治疗时应该密切观察。 应警告司机和机械操作者，使用本品可能会引起头晕或思睡。
【 儿童用药】	不适用。
【 老年患者用药】	不适用。
【 孕妇及哺乳期妇女用药】	妊娠期用药 ：如果黄体缺乏，可在妊娠头3个月使用本品。 哺乳期用药 ：哺乳期间请勿使用本品。
【 不良反应】	发生率≥5％的不良反应包括 ： 全身 ：腹痛、会阴部疼痛。 中枢与周围神经系统 ：头痛。 消化系统 ：便秘、腹泻、恶心、呕吐。 肌肉骨骼系统 ：关节疼痛。 精神 ：抑郁、性欲减退、紧张、思睡。 女性生殖系统 ：乳房增大、性交困难。 泌尿系统 ：夜尿症。 发生率<5％的不良反应包括 ： 自主神经系统 ：口干、多汗。 全身 ：哭泣、过敏、变态反应、食欲降低、乏力、水肿、面部水肿、发热、潮热、流感样症状、水潴留。 心血管系统 ：晕厥。 中枢与周围神经系统 ：偏头痛、震颤。 呼吸系统 ：哮喘、呼吸困难、换气过度、鼻炎、咽炎、窦炎。 消化系统 ：消化不良、嗳气、肠胃气胀、胃炎、牙痛。 代谢和营养 ：烦渴。 泌尿系统 ：膀胱炎、排尿困难、尿频、尿路感染。 肌肉骨骼系统 ：下肢痉挛、下肢痛、骨痛。 血液系统 ：贫血、紫癜。 肿瘤 ：良性囊肿。 女性生殖系统 ：痛经、经前期紧张、阴道干燥。 皮肤 ：痤疮、瘙痒、皮疹、皮脂溢出、皮肤色素变化、皮肤疾病、荨麻疹。 精神 ：攻击性反应、健忘、失眠症。 眼部 ：结膜炎、干眼病。
【 药物相互作用】	本药与其它药物之间不存在相互作用。 本品不应和其他局部阴道制剂同时使用。如果同时使用其它局部阴道制剂，请在本药给药之前或之后6个小时使用。 查看 雪诺同8％
【 Crinone8％】	详细药物相互作用信息 FDA妊娠分级  口服使用时 B级：在动物繁殖研究中（并未进行孕妇的对照研究），未见到药物对胎儿的不良影响。或在动物繁殖性研究中发现药物有副作用，但这些副作用并未在设对照的、妊娠首３个月的妇女中得到证实（也没有在其后６个月具有危害性的证据）。
【 药理作用】	黄体酮是由卵巢、胎盘和肾上腺分泌的一种天然类固醇激素。当具有足够的雌激素时，黄体酮可使子宫内膜由增殖期改变为分泌期。黄体酮是蜕膜组织发育中的主要物质，有关黄体酮对腺上皮细胞和间质分化的作用已经进行了广泛的研究。黄体酮是增加子宫内膜对孕卵着床接受性必不可少的成分，在受精卵着床后，黄体酮还起到维持妊娠的作用。口服雌二醇和肌肉注射黄体酮可以使功能性无生殖腺妇女在50-60岁期间产生正常或几乎正常的子宫内膜应答反应。
【 临床试验】	在国外进行了两项临床试验。一项为多中心、开放性临床研究（COL 1620-F01），旨在比较本品与黄体酮口服制剂在体外受精（IVF）受试者中的有效性及安全性。共入选283例受试者。移植后24小时内开始给药，黄体酮口服制剂组每早给予100 mg，每晚给予200 mg；黄体酮阴道缓释凝胶组90 mg每日给药1次至30天。结果 ：两组妊娠率无显著性差异（黄体酮阴道缓释凝胶组 ：35％，口服黄体酮制剂组 ：30％，p=0.31）。 另一项为单中心，平行、随机、开放临床研究（COL1620-007US），旨在评价本品对POF（卵巢早衰）或仅有部分卵巢功能受试者在赠卵周期中诱导、促进及维持妊娠的有效性及安全性。共入选90例受试者，随机给予黄体酮阴道缓释凝胶90 mg(n=64)每日2次，或肌肉注射黄体酮100 mg(n=26)每日1次。试验共3个周期（预备周期、赠卵周期及治疗期）。结果 ：黄体酮阴道缓释凝胶组27例（54％）为化学妊娠，其中24例（48％）为临床妊娠。在临床妊娠的24例受试者中，15例（30％）为持续妊娠。肌肉注射黄体酮组有4例（31％）化学妊娠，其中3例（23％）为临床妊娠。临床妊娠的3例受试者中，2例（15％）为持续妊娠。 在中国进行了一项随机、开放、多中心、对照临床研究，以评价本品的安全性及有效性。试验共入选238例受试者，其中黄体酮阴道缓释凝胶组117例，黄体酮注射液组121例。黄体酮阴道缓释凝胶90 mg每日1次，黄体酮注射液60 mg每日1次，连续使用60天。结果表明，两组在胚胎移植后14日血hCG阳性率、胚胎移植后30天及60天的临床妊娠率均无统计学差异。
【 毒理研究】	致癌作用、致突变、生育力损害 ：目前还未进行本药的致癌性、致突变性的非临床毒性研究。本药对生育力的作用也未在动物中进行评价。
【 药代动力学】	吸收 ：由于本药的持续释放特性，黄体酮的吸收延长，吸收半衰期约为25-50小时，清除半衰期为5-20分钟。因此，本药药代动力学特征受吸收率的影响作用比清除率大。 与肌肉注射的黄体酮为对照、对本药中的黄体酮生物利用度进行了检测。在一项单剂量的交叉试验研究中，20名经雌激素治疗的健康绝经后妇女以雪诺同8％阴道给予90 mg黄体酮、或接受肌肉注射90 mg黄体酮。药代动力学参数（均值±标准偏差）如下。 最大血清浓度（Cmax） ：本药8％组为14.87±6.32 ng/mL；90 mg肌肉注射黄体酮为53.76±14.9 ng/mL。 24小时平均血清浓度（Cavg 0-24） ：本药8％组为6.98±3.21 ng/mL；90 mg肌肉注射黄体酮为28.98±8.75 ng/mL。 给药0-96小时后药物浓度时间曲线下面积（AUC0-96） ：本药8％组为296.78±129.90 ng/hr/mL；90 mg肌肉注射黄体酮为1378.91±176.39 ng/hr/mL。 达峰时间（Tmax） ：本药8％组为6.8±3.3小时 ；90 mg肌肉注射黄体酮为9.2±2.7小时。 消除半衰期（T1/2） ：本药8％组为34.8±11.3小时 ；90 mg肌肉注射黄体酮为19.6±6.0小时。 相对生物利用度（F） ：2组均为19.8％。 对10名经激素治疗的健康绝经后妇女进行了多剂量药代动力学研究，每天给予1次或每天给予2次本药共12天的研究。治疗开始后的24小时内即达到了稳态。从这些研究中最后给予本药得到的药代动力学参数（均值±标准偏差）如下。 辅助生殖技术 最大血清浓度（Cmax） ：每日1次组为15.97±5.05 ng/mL；每日2次组为14.57±4.49 ng/mL。 平均血清浓度（Cavg） ：每日1次组为8.99±3.53 ng/mL；每日2次组为11.6±3.47 ng/mL。 达峰时间（Tmax） ：每日1次组为5.40±0.97小时 ；每日2次组为3.55±2.48小时。 药物浓度时间曲线下面积（AUC0-t） ：每日1次组为391.98±153.28 ng/hr/mL；每日2次组为138.72±41.58 ng/hr/mL。 消除半衰期（T1/2） ：每日1次组为45.00±34.70小时 ；每日1次组为25.91±6.15小时。 分布 ：黄体酮几乎完全与血清蛋白结合（大约96-99％），主要是血清白蛋白和皮质类固醇结合球蛋白。 代谢 ：口服黄体酮后的尿中主要代谢产物为5β-孕甾烷-3α，在血浆中仅以结合形式出现的代谢产物为20α-二醇葡糖苷酸。血浆代谢产物还包括5β-孕甾烷-3α-醇-20-酮（5β-孕甾烷醇酮）和5α-孕甾烷-3α-醇-20-酮（5α-孕甾烷醇酮）。 排泄 ：黄体酮通过胆汁和肾脏两种途径进行清除。在注射标记的黄体酮后，有50-60％的黄体酮代谢产物会经过肾脏排泄 ；有大约10％会通过胆汁和粪便（即第二个主要排泄途径）进行排泄。标记物的总回收率为给药剂量的70％，对剩余剂量中的排泄物还未进行鉴定。只有少量是以黄体酮原形物质从胆汁中进行排泄。
【 贮藏】	密闭，置于25°C以下。
【 有效期】	有效期36个月。
【 生产企业】	企业名称：英国Fleet laboratories Limited

 

CRINONE® 4% and 8%
(progesterone) Gel
For Vaginal Use Only

Crinone® (progesterone gel) is a bioadhesive vaginal gel containing micronized progesterone in an emulsion system, which is contained in single use, polypropylene vaginal applicators. The carrier vehicle is an oil in water emulsion containing the water swellable, but insoluble polymer, polycarbophil. The progesterone is partially soluble in both the oil and water phase of the vehicle, with the majority of the progesterone existing as a suspension. Physically, Crinone has the appearance of a soft, white to off-white gel.

The active ingredient, progesterone, is present in either a 4% or an 8% concentration (w/w). The chemical name for progesterone is pregn-4-ene-3,20-dione. It has an empirical formula of C21H30O2and a molecular weight of 314.5.

The structural formula is:

Progesterone exists in two polymorphic forms. Form 1, which is the form used in Crinone, exists as white orthorhombic prisms with a melting point of 127-131°C.

Each applicator delivers 1.125 grams of Crinone gel containing either 45 mg (4% gel) or 90 mg (8% gel) of progesterone in a base containing glycerin, light mineral oil, polycarbophil, carbomer homopolymer Type B, hydrogenated palm oil glyceride, sorbic acid, purified water and may contain sodium hydroxide.

c

 

 

 

 

Crinone 8% is indicated for progesterone supplementation or replacement as part of an Assisted Reproductive Technology ("ART") treatment for infertile women with progesterone deficiency.

Crinone 4% is indicated for the treatment of secondary amenorrhea. Crinone 8% is indicated for use in women who have failed to respond to treatment with Crinone 4%.

Crinone 8% is administered vaginally at a dose of 90 mg once daily in women who require progesterone supplementation. Crinone 8% is administered vaginally at a dose of 90 mg twice daily in women with partial or complete ovarian failure who require progesterone replacement. If pregnancy occurs, treatment may be continued until placental autonomy is achieved, up to 10 to 12 weeks.

Crinone 4% is administered vaginally every other day up to a total of six doses. For women who fail to respond, a trial of Crinone 8% every other day up to a total of six doses may be instituted.

It is important to note that a dosage increase from the 4% gel can only be accomplished by using the 8% gel. Increasing the volume of gel administered does not increase the amount of progesterone absorbed.

Crinone is available in the following strengths:

4% gel (45 mg) in a single use, disposable, white polypropylene vaginal applicator with a teal twist-off cap. Each applicator contains 1.3 g of gel and delivers 1.125 g of gel.

NDC 52544-255-24: 6 Single-use prefilled applicators.

8% gel (90 mg) in a single use, disposable, white polypropylene vaginal applicator with a teal twist-off cap. Each applicator contains 1.3 g of gel and delivers 1.125 g of gel.

NDC 52544-256-12: 15 Single-use prefilled applicators.

Each applicator is wrapped and sealed in a foil overwrap.

Store at 20-25°C (68-77°F). [See USP controlled room temperature.]

Keep out of reach of children.

Distributed By: Actavis Pharma, Inc.Parsippany,NJ07054USA. Revised: Auf 2014

 

 

 

In a study of 61 women with ovarian failure undergoing a donor oocyte transfer procedure receiving Crinone 8% twice daily, treatment-emergent adverse events occurring in 5% or more of the women are shown in Table 3.

TABLE 3 - Treatment-Emergent Adverse Events in ≥ 5% of Women Receiving Crinone 8% Twice Daily Study COL1620-007US (n = 61)

In a second clinical study of 139 women using Crinone 8% once daily for luteal phase support while undergoing an in vitro fertilization procedure, treatment-emergent adverse events reported in ≥ 5% of the women are shown in Table 4.

TABLE 4 - Treatment-Emergent Adverse Events in ≥ 5% of Women Receiving Crinone 8% Once Daily Study COL1620-F01 (n = 139)

In three studies, 127 women with secondary amenorrhea received estrogen replacement therapy and Crinone 4% or 8% every other day for six doses. Treatment-emergent adverse events during estrogenand Crinone treatment that occurred in 5% or more of women are shown in Table 5.

TABLE 5 - Treatment-Emergent Adverse Events in ≥ 5% of Women Receiving Estrogen Treatment and Crinone Every Other Day Studies COL1620-004US, COL1620-005US, COL1620-009US

No drug interactions have been assessed with Crinone.

 

 

 

 

The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis,cerebrovascular disorders, pulmonary embolism, and retinal thrombosis). Should any of these occur or be suspected, the drug should be discontinued immediately.

Progesterone and progestins have been used to prevent miscarriage in women with a history ofrecurrent spontaneous pregnancy losses. No adequate evidence is available to show that they are effective for this purpose.

The pretreatment physical examination should include special reference to breast and pelvicorgans, as well as Papanicolaou smear.In cases of breakthrough bleeding, as in all cases of irregular vaginal bleeding, nonfunctional causes should be considered. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures should be undertaken.Because progestogens may cause some degree of fluid retention, conditions which might be influenced by this factor (e.g., epilepsy, migraine, asthma, cardiac or renal dysfunction) require careful observation.The pathologist should be advised of progesterone therapy when relevant specimens are submitted.Patients who have a history of psychic depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.A decrease in glucose tolerance has been observed in a small percentage of patients on estrogenprogestin combination drugs. The mechanism of this decrease is not known. For this reason, diabetic patients should be carefully observed while receiving progestin therapy.

The product should not be used concurrently with other local intravaginal therapy. If other local intravaginal therapy is to be used concurrently, there should be at least a 6-hour period before or after Crinone administration. Small, white globules may appear as a vaginal discharge possibly due to gel accumulation, even several days after usage.

Nonclinical toxicity studies to determine the potential of Crinone to cause carcinogenicity or mutagenicity have not been performed. The effect of Crinone on fertility has not been evaluated in animals.

[See Clinical Studies, Assisted Reproductive Technology]

Crinone 8% has been used to support embryo implantation and maintain pregnancies through its use as part of ART treatment regimens in two clinical studies (studies COL1620-007US and COL1620-F01). In the first study (COL1620-007US), 54 Crinone-treated women had donor oocyte transfer procedures, and clinical pregnancies occurred in 26 women (48%). The outcomes of these 26 pregnancies were as follows: one woman had an elective termination of pregnancy at 19 weeks due to congenitalmalformations (omphalocele) associated with a chromosomal abnormality; one woman pregnant with triplets had an elective termination of her pregnancy; seven women had spontaneous abortions; and 17 women delivered 25 apparently normal newborns.

In the second study (COL1620-F01), Crinone 8% was used in the luteal phase support of women undergoing in vitro fertilization ("IVF") procedures. In this multi-center, open-label study, 139 women received Crinone 8% once daily beginning within 24 hours of embryo transfer and continuing through Day 30 post-transfer.

Clinical pregnancies assessed at Day 90 post-transfer were seen in 36 (26%) of women. Thirty-two women (23%) delivered newborns and four women (3%) had spontaneous abortions. Of the 47 newborns delivered, one had a teratoma associated with a cleft palate; one had respiratory distress syndrome; 44 were apparently normal and one was lost to follow-up.

The safety and effectiveness in geriatric patients (over age 65) have not been established.

Safety and effectiveness in pediatric patients have not been established.

Detectable amounts of progestins have been identified in the milk of mothers receiving them. The effect of this on the nursing infant has not been determined.

Overdosage & Contraindications

There have been no reports of overdosage with Crinone. In the case of overdosage, however, discontinue Crinone, treat the patient symptomatically, and institute supportive measures.

As with all prescription drugs, this medicine should be kept out of the reach of children.

Crinone should not be used in individuals with any of the following conditions:

Known sensitivity to Crinone (progesterone or any of the other ingredients)Undiagnosed vaginal bleedingLiver dysfunction or diseaseKnown or suspected malignancy of the breast or genital organsMissed abortionActive thrombophlebitis or thromboembolic disorders, or a history of hormone-associated thrombophlebitis or thromboembolic disorders

Clinical Pharmacology

Progesterone is a naturally occurring steroid that is secreted by the ovary, placenta, and adrenal gland. In the presence of adequate estrogen, progesterone transforms a proliferative endometrium into a secretory endometrium. Progesterone is essential for the development of decidual tissue, and the effect of progesterone on the differentiation of glandular epithelia and stroma has been extensively studied.

Progesterone is necessary to increase endometrial receptivity for implantation of an embryo. Once an embryo is implanted, progesterone acts to maintain the pregnancy. Normal or near-normal endometrial responses to oral estradiol and intramuscular progesterone have been noted in functionally agonadal women through the sixth decade of life. Progesterone administration decreases the circulatory levels of gonadotropins.

Absorption

Due to the sustained release properties of Crinone, progesterone absorption is prolonged with an absorption half-life of approximately 25 to 50 hours, and an elimination half-life of 5 to 20 minutes. Therefore, the pharmacokinetics of Crinone are rate-limited by absorption rather than by elimination.

The bioavailability of progesterone in Crinone was determined relative to progesterone administered intramuscularly. In a single dose crossover study, 20 healthy, estrogenized postmenopausal women received 45 mg or 90 mg progesterone vaginally in Crinone 4% or Crinone 8%, or 45 mg or 90 mg progesterone intramuscularly. The pharmacokinetic parameters (mean ± standard deviation) are shown in Table 1.

TABLE 1 Single Dose Relative Bioavailability

The multiple dose pharmacokinetics of Crinone 4% and Crinone 8% administered every other day and Crinone 8% administered daily or twice daily for 12 days were studied in 10 healthy, estrogenized postmenopausal women in two separate studies. Steady state was achieved within the first 24 hours after initiation of treatment. The pharmacokinetic parameters (mean ± standard deviation) after the last administration of Crinone 4% or 8% derived from these studies are shown in Table 2.

TABLE 2 Multiple Dose Pharmacokinetics

Distribution

Progesterone is extensively bound to serum proteins (~ 96-99%), primarily to serum albumin andcorticosteroid binding globulin.

Metabolism

The major urinary metabolite of oral progesterone is 5β-pregnan-3α, 20α-diol glucuronide which is present in plasma in the conjugated form only. Plasma metabolites also include 5β-pregnan-3α-ol-20-one (5β-pregnanolone) and 5α-pregnan-3α-ol-20-one (5α-pregnanolone).

Excretion

Progesterone undergoes both biliary and renal elimination. Following an injection of labeled progesterone, 50-60% of the excretion of progesterone metabolites occurs via the kidney; approximately 10% occurs via the bile and feces, the second major excretory pathway. Overall recovery of labeled material accounts for 70% of an administered dose, with the remainder of the dose not characterized with respect to elimination. Only a small portion of unchanged progesterone is excreted in the bile.

Assisted Reproductive Technology

In a single-center, open-label study (COL1620-007US), 99 women (aged 28-47 years) with either partial (n = 84) or premature ovarian failure (n = 15) who were candidates to receive a donor oocyte transfer as an Assisted Reproductive Technology ("ART") procedure were randomized to receive either Crinone 8% twice daily (n = 68) or intramuscular progesterone 100 mg daily (n = 31). The study was divided into three phases (Pilot, Donor Egg and Treatment). The first phase of the study consisted of a test Pilot Cycle to ensure that the administration of transdermal estradiol and progesterone would adequately prime the endometrium to receive the donor egg. The second phase was the Donor Egg Cycle during which a fertilized oocyte was implanted. Crinone 8% was administered beginning the evening of Day 14 of the Pilot and Donor Egg cycles. Subjects with partial ovarian function also underwent a Pre-Pilot Cycle and a Pre-Donor Egg Cycle during which time they were administered only leuprolide acetate to suppress remaining ovarian function. The Pre-Pilot Cycle, Pilot Cycle, Pre- Donor Egg Cycle, and Donor Egg Cycle each lasted approximately 34 days. The third phase of the study consisted of a 10-week treatment period to maintain a pregnancy until placental autonomy was achieved.

Sixty-one women received Crinone 8% as part of the Pilot Cycle to determine their endometrial response. Of the 55 evaluable endometrial biopsies in the Crinone 8% group performed on Day 25 to 27, all were histologically "in-phase", consistent with luteal phase biopsy specimens of menstruating women at comparable time intervals. Fifty-four women who received Crinone 8% and had a histologically "in-phase" biopsy received a donor oocyte transfer. Among these 54 Crinone-treated women, clinical pregnancies (assessed about week 10 after transfer by clinical examination, ultrasound and/or ß-hCG levels) occurred in 26 women (48%). Seventeen women (31%) delivered a total of 25 newborns, seven women (13%) had spontaneous abortions and two women (4%) had elective abortions.

In a second study (COL1620-F01), Crinone 8% was used in luteal phase support of women with tubal oridiopathic infertility due to endometriosis and normal ovulatory cycles, undergoing in vitro fertilization("IVF") procedures. All women received a GnRH analog to suppress endogenous progesterone, human menopausal gonadotropins, and human chorionic gonadotropin. In this multi-center, open-label study, 139 women (aged 22-38 years) received Crinone 8% once daily beginning within 24 hours of embryo transfer and continuing through Day 30 post-transfer. Clinical pregnancies assessed at Day 90 posttransfer were seen in 36 (26%) of women. Thirty-two women (23%) delivered newborns and four women (3%) had spontaneous abortions. (See PRECAUTIONS, Pregnancy)

Secondary Amenorrhea

In three parallel, open-label studies (COL1620-004US, COL1620-005US, COL1620-009US), 127 women (aged 18-44) with hypothalamic amenorrhea or premature ovarian failure were randomized to receive either Crinone 4% (n = 62) or Crinone 8% (n = 65). All women were treated with either conjugated estrogens 0.625 mg daily (n = 100) or transdermal estradiol (delivering 50 mcg/day) twice weekly (n = 27).

Estrogen therapy was continuous for the entire three 28-day cycle studies. At Day 15 of the second cycle (six weeks after initiating estrogen replacement), women who demonstrated adequate response to estrogen therapy (by ultrasound) and who continued to be amenorrheic received Crinone every other day for six doses (Day 15 through Day 25 of the cycle).

In cycle 2, Crinone 4% induced bleeding in 79% of women and Crinone 8% induced bleeding in 77% of women. In the third cycle, estrogen was continued and Crinone was administered every other day beginning on Day 15 for six doses. On Day 24 an endometrial biopsy was performed. In 53 women who received Crinone 4%, biopsy results were as follows: 7% proliferative, 40% late secretory, 19% mid secretory, 13% early secretory, 7% atrophic, 6% menstrual endometrium, 6% inactive endometrium and 2% negative endometrium. In 54 women who received Crinone 8%, biopsy results were as follows: 44% late secretory, 19% mid secretory, 11% early secretory, 19% atrophic, 5% menstrual endometrium and 2% "oral contraceptive like" endometrium.

Medication Guide

Crinone® 4% and Crinone® 8%
(progesterone) Gel

For Vaginal Use Only

Please read this information carefully before you start to use Crinone and each time your prescription is renewed, in case anything has changed. This leaflet does not take the place of discussions with your doctor. If you still have any questions, ask your doctor or healthcare provider.

What is Crinone?

Crinone is medicine that contains the female hormone called progesterone.

What is Crinone used for?

Crinone 4% and Crinone 8% are used to treat the absence of a menstrual period in a woman who has previously had a menstrual period. Progesterone is one of the hormones that allows women to have regular menstrual periods. When you do not produce enough progesterone, menstrual irregularities can occur. Crinone may be prescribed to increase your progesterone.Crinone 8% is also used as part of a program for women who are undergoing fertility treatments to get pregnant. Progesterone is one of the hormones that helps to prepare the lining of your uterusso that it is ready to receive and nourish a fertilized egg and to continue a pregnancy. If you are undergoing ART treatment and your doctor has determined your body does not produce enough progesterone on its own, Crinone may be prescribed to increase your progesterone.If pregnancy occurs, Crinone may be supplemented for 10 to 12 weeks until production of progesterone by the placenta is adequate.

Who should not use Crinone?

Do not start using Crinone if you:

Are allergic to progesterone, progesterone-like drugs, or any of the inactive ingredients in the gel (ask a pharmacist if you are not sure about the inactive ingredients in Crinone).Have unusual vaginal bleeding which has not been evaluated by a doctor.Have or have had a liver disease.Have or have had cancer of the breast or genital organs.Have had a miscarriage and your physician suspects some tissue is still in the uterus.Have or have had blood clots in the legs, lungs, eyes, or elsewhere.

What are the possible side effects of Crinone?

Serious side effects include:

Blood clots. Progestational drug products may increase your chance of having blood clots in your blood vessels. Blood clots can cause:blood vessel problems (thrombophlebitis)strokeloss of your arm or legblood clot in your lungs (pulmonary embolus)heart attackdeathBirth defects. Abdominal wall defect and cleft palate have been reported with Crinone use in early pregnancy. It is not known if these defects were caused by Crinone.

Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:

Pains in the calves or chest, a sudden shortness of breath or coughing blood indicating possible clots in the legs, heart, or lungs.Severe headache or vomiting, dizziness, faintness, or changes in vision or speech, weakness or numbness of an arm or leg indicating possible clots in the brain or eye.

Common side effects include:

abdominal painperineal pain (the perineum is the area between the vagina and the rectum)crampsbloatingheadachefatigueincreased appetitecontstipationdiarrheanauseajoint paindepressionmood swingssleep disordernervousnessdecreased libidobreast enlargementexcessive urination at nightvaginal dischargeupper respiratory tract infection

These are not all the possible side effects of Crinone. For more information, ask your healthcare provider or pharmacist for advice about side effects. You may report s ide effects to FDA at 1-800- FDA-1088.

How should I use Crinone?

Use as directed by your healthcare provider.

Read the Instructions for Use included in this leaflet for information on the right way to use Crinone.

Additional information about Crinone

You may see a small amount of white discharge that may look like a vaginal discharge. This discharge may be caused by gel that can remain in your vagina, even several days after use. Gel discharge from your vagina is normal, but if you are concerned, talk to your healthcare provider.If you miss a dose of Crinone, use it as soon as you remember.Do not use more Crinone than the dose prescribed by your doctor.Talk to your healthcare provider about whether to use other vaginal medicines when you are using Crinone.

General information about the safe and effective use of Crinone

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use Crinone for another condition. Your doctor has prescribed this drug for you and you alone. Do not give this drug to anyone else, even if they have the same condition.

Keep Crinone out of the reach of children

This leaflet provides the most important information about Crinone. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Crinone that is written for health professionals.

You can get more information by calling the toll free number 1-888-776-4358 or visit www.crinoneusa.com.

What are the ingredients in Crinone?

Crinone contains either 45 mg (4% gel) or 90 mg (8% gel) of progesterone in a base containing glycerin, light mineral oil, polycarbophil, carbomer homopolymer Type B, hydrogenated palm oil glyceride, sorbic acid, purified water and may contain sodium hydroxide.

How should I store Crinone?

Store Crinone at room temperature between 68°F to 77°F (20°C to 25°C).

Do not use Crinone after the expiration date printed on the box.

INSTRUCTIONS FOR USE

Crinone® 4% and Crinone® 8% ("KRI-noan")

(progesterone gel)

For Vaginal Use Only

You will need the following supplies : See Figure A.

Step 1. Remove the applicator from the sealed wrapper.

Open the sealed wrapper and remove the applicator. Do not remove the twist-off cap at this time.See Figure B.

Step 2. Insert the plunger into the open end of the applicator. See Figure C.

Hold the applicator on each side and push the plunger into the applicator until the plunger snaps into place.You will see about 1 inch of the plunger outside of the applicator.

Step 3. Remove the cap. See Figures D and E.

Remove the cap from the tip of the applicator by twisting it counterclockwise.Do not push the plunger while you are removing the cap. This could cause some gel to come out.

Step 4. Prepare to insert the applicator. See Figure F.

Choose the position that is most comfortable for you. For example, lying down on your back with your knees bent.

Step 5. Insert the applicator. See Figure G.

After you are in a comfortable position, gently insert the rounded tip of the applicator into your vagina.

Step 6. Push the plunger. See Figure H.

While the applicator is inserted in your vagina, push the plunger to release the gel into your vagina.

Step 7. Remove the applicator from your vagina and throw it away in your household trash.

It is normal for a small amount of gel to be left in the applicator. You will still get the right dose of medicine.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.