ReprosTherapeutics公司表示应美国FDA的要求已经递交了enclomiphene（Androxal）修改后的适应证申请，本品作为一种低剂量睾丸激素疗法寻求用于治疗男性性腺机能减退。修改后的适应证为：本品用于在男性性腺机能减退治疗中睾丸激素水平低而希望维持生殖能力的患者。 本品的有效成分为enclomiphene，为一种枸橼酸氯米芬（克罗米芬）反式立体异构体，分子结构酷似睾丸素从而可替代睾丸素。 Androxal（enclomiphene）增强了睾丸激素水平低的男子的精子计数：ReprosRepros'Androxal还发现，男性提高男性荷尔蒙睾丸激素Enclomiphene柠檬酸（Androxal）可以显着增加精子数量，同时增加男性睾酮水平，声称其生产Repros治疗公司 Enclomiphene柠檬酸（Androxal）进行了研究其疗效和安全性功能减退与中学谁正在接受激素替代治疗男性的研究。 二级功能减退是缺乏国家，其中男性荷尔蒙睾丸激素低于正常范围去，即使是在老年男性，因受到垂体对睾丸不够刺激。 Repros相比其口服制剂enclomiphene柠檬酸（Androxal）经批准的局部睾酮凝胶Testim1％Auxilium制药公司在为有缺陷或内源性睾酮缺乏相关条件的成年男性睾丸激素替代疗法表示。 Repros进行了两个中心，三个臂，随机，开放标签，固定剂量，主动控制，证明性的原则46和51之间的男性研究岁谁与治疗睾丸激素凝胶局部以前。 研究结果发现，Androxal始终把提高精子数量正常范围后，第3和6个月的治疗和后续行动。 Testim导致精子数低于20 × 106/ml（水平低于该男子将被视为不育），于3个月的5名男子。在6个月，在5Testim治疗男性3仍远低于20 × 106/ml水平表现出很少或几乎没有检测精子数量，而另外两个显示层次“20 × 106/ml。 精子数量有显着高于Androxal比Testim治疗3和6个组。 Androxal还发现增加两个leutenising素（LH），卵泡刺激素（FSH），而男子的Testim激素有关的这些重要的生育率非常低的水平。 Androxal已经表现出LH和FSH有效的长期研究了一年多，在男性性腺继发。 新Androxal研究证实，睾丸激素水平可通过内源性睾酮正常化而恢复生育能力，Repros报告。 “Androxal可以填补一个没有毒品的需要，能够恢复睾丸功能，同时提供好处的睾丸激素正常化规定hypogonadal男子博士说：”杰德Kaminetsky（泌尿科，纽约大学医学中心部） ，在正式发布主要调查。 与Androxal和Testim待遇以及容忍在这项研究中，很少被报道的副作用。 Repros计划提交一份美国FDA会议要求，以确定是否该机构认为这些意见是临床相关的发展计划是否可以设计，以确认这种探索性研究的结果，并最终支持为治疗标签中学男性性腺功能减退谁希望保存自己的生育能力。 今年9月，美国FDA要求对摄制的禁毒Proellex导致更多的数据，以解决临床对它举行，由于安全原因。 Proellex是一种选择性的孕激素受体阻滞剂，以前主要是正在为子宫肌瘤和子宫内膜异位症相关症状长期治疗药物。 在2008年Repros提交了Proellex了作为三贫血由于月经过多与子宫肌瘤相关一个月前的妇女手术治疗新的适应症的研究性新药申请（印度）。 在2009年8月3日，Repros治疗宣布自愿暂停了其在临床试验Proellex所有患者的剂量。 局部激素的使用已与垂体性腺激素的抑制，促黄体生成素（LH），卵泡刺激素（FSH）睾酮都刺激生产和睾丸精子必要的。 Androxal是一种口服治疗的目的是恢复正常的脑，垂体，睾丸相互作用，从而睾丸功能的二次功能减退的男子。 总部设在兀兰，得克萨斯州，Repros治疗的重点是口服的小分子药物，治疗男性和女性生殖系统疾病的发展。  enclomiphene申请用于男性性腺机能减退ReprosTherapeutics公司表示应FDA的要求已经递交了enclomiphene（Androxal）修改后的适应证申请，本品作为一种低剂量睾丸激素疗法寻求用于治疗男性性腺机能减退。修改后的适应证为：本品用于在男性性腺机能减退治疗中睾丸激素水平低而希望维持生殖能力的患者。 本品的有效成分为enclomiphene，为一种枸橼酸氯米芬(clomiphene citrate )反式立体异构体，分子结构酷似睾丸素从而可替代睾丸素。        Androxal - General Information: A triphenyl ethylene stilbene derivative which is an estrogen agonist orantagonist depending on the target tissue. [PubChem]Pharmacology: Androxal (previously clomiphene)isanorallyadministered, non steroidal, ovulatory stimulant that acts as a selective estrogen receptor modulator (SERM). Androxal can lead to multiple ovulation, and hence increasing the risk of twins. In comparison to purified FSH, the rate of ovarian hyperstimulation syndrome is low. There may be an increased risk of ovarian cancer, and weight gain. Androxal is capable of interacting with estrogen-receptor-containing tissues, including the hypothalamus, pituitary, ovary, endometrium, vagina, and cervix. It may compete with estrogen for estrogen-receptor-binding sites and may delay replenishment of intracellular estrogen receptors. Androxal initiates a series of endocrine events culminating in a preovulatory gonadotropin surge and subsequent follicular rupture. The first endocrine event in response to a course of clomifene therapy, is an increase in the release of pituitary gonadotropins. This initiates steroidogenesis and folliculogenesis resulting in growth of the ovarian follicle and an increase in the circulating level of estradiol. Following ovulation, plasma progesterone and estradiol rise and fall as they would in a normal ovulatory cycle. Androxal for patientsThe purpose and risks of clomiphene citrate tablets USP therapy should be presented to the patient before starting treatment. It should be emphasized that the goal of clomiphene citrate tablets USP therapy is ovulation for subsequent pregnancy. The physician should counsel the patient with special regard to the following potential risks: Visual Symptoms: Advise that blurring or other visual symptoms occasionally may occur during or shortly after clomiphene citrate tablets USP therapy. Warn that visual symptoms may render such activities as driving a car or operating machinery more hazardous than usual,particularly under conditions of variable lighting. The patient should be instructed to inform the physician whenever any unusual visual symptoms occur. If the patient has any visual symptoms, treatment should be discontinued and complete ophthalmologic evaluation performed. Abdominal Pelvic Pain or Distention: Ovarian enlargement may occur during or shortly after therapy with clomiphene citrate tablets USP. To minimize the risks associated with ovarian enlargement, the patient should be instructed to inform the physician of any abdominal or elvic pain, weight gain, discomfort, or distention after taking clomiphene citrate tablets USP. Multiple Pregnancy: Inform the patient that there is an increased chance of multiple pregnancy, including bilateral tubal pregnancy and coexisting tubal and intrauterine pregnancy, when conception occurs in relation to clomiphene citrate tablets USP therapy. The potential complications and hazards of multiple pregnancy should be explained. Pregnancy Wastage and Birth Anomalies: The physician should explain the assumed risk of any pregnancy, whether ovulation is induced with the aid of clomiphene citrate tablets USP or occurs naturally. The patient should be informed of the greater risks associated with certain characteristics or conditions of any pregnant woman, eg, age of female and male partner, history of spontaneous abortions, Rh genotype, abnormal menstrual history, infertility history, organic heart disease, diabetes, exposure to infectious agents such as rubella, familial history of birth anomaly, that may be pertinent to the patient for whom clomiphene citrate tablets USP is being considered. Based upon the evaluation of the patient, genetic counseling may be indicated. The overall incidence of reported birth anomalies from pregnancies associated with maternal clomiphene citrate tablets USP ingestion duringtheinvestigational studies was within the range of that reported in published references for the general population.During clinical investigation, the experience from patients with known pregnancy outcome (Table 1) shows a spontaneous abortion rate of 20.4% and stillbirth rate of 1.0%..Androxal InteractionsDrug interactions with clomiphene citrate tablets USP have not been documented. Androxal Contraindications Hypersensitivity CLOMID is contraindicated in patients with a known hypersensitivity or allergy to clomiphene citrate or to any of its ingredients. Pregnancy CLOMID should not be administered during pregnancy. CLOMID may cause fetal harm in animals. Although no causative evidence of a deleterious effect of CLOMID therapy on the human fetus has been established, there have been reports of birth anomalies which, during clinical studies, occurred at an incidence within the range reported for the general population. To avoid inadvertent CLOMID administration during early pregnancy, appropriate tests should be utilized during each treatment cycle to determine whether ovulation occurs. The patient should be evaluated carefully to exclude pregnancy,ovarianenlargement,orovarian cyst formation between each treatment cycle. The next course of CLOMID therapy should be delayed untilthese conditions have been excluded. Fetal/Neonatal Anomalies and Mortality. The following fetal abnormalities have been reported subsequent to pregnancies following ovulation induction therapy with CLOMID during clinical trials. Each of the following fetal abnormalities were reported at a rate of < 1% (experiences are listed in order of decreasing frequency): Congenitalheartlesions,Downsyndrome,clubfoot,congenitalgutlesions,hypospadias,microcephaly, harelip and cleft palate, congenital hip,hemangioma, undescended testicles, polydactyly, conjoined twins and teratomatous malformation, patentductusarteriosus, amaurosis, arteriovenous fistula, inguinal hernia, umbilical hernia, syndactyly,pectusexcavatum,myopathy, dermoid cyst of scalp, omphalocele, spina bifida occulta, ichthyosis, and persistent lingual frenulum. Neonatal death and fetal death/stillbirth in infants with birth defects have also been reported at a rate of < 1%. The overall incidence of reported birth anomalies from pregnancies associated with maternal CLOMID ingestion during clinical studies was within the range of that reported for the general population. In addition, reports of birth anomalies have been received during postmarketing surveillance of CLOMID. Animal Fetotoxicity. Oral administration of clomiphene citrate to pregnant rats during organogenesis at doses of 1 to 2 mg/kg/day resulted in hydramnion and weak, edematous fetuses with wavy ribs and other temporary bone changes. Doses of 8 mg/kg/day or more also caused increased resorptions and dead fetuses, dystocia, and delayed parturition, and 40 mg/kg/day resulted in increased maternal mortality. Single doses of 50 mg/kg caused fetal cataracts, while 200 mg/kg caused cleft palate. Following injection of clomiphene citrate 2 mg/kg to mice and rats during pregnancy, the offspring exhibited metaplastic changes of the reproductive tract. Newborn mice and rats injected during the first few days of life also developed metaplastic changes in uterine and vaginal mucosa, as well as premature vaginal opening and anovulatory ovaries. These findings are similar to the abnormalreproductive behavior and sterility described with other estrogens and antiestrogens. In rabbits, some temporary bone alterations were seen in fetuses from dams given oral doses of 20 or 40 mg/kg/day during pregnancy, but not following 8 mg/kg/day. No permanent malformations were observed in those studies. Also, rhesus monkeys given oral doses of 1.5 to 4.5 mg/kg/day for various periods during pregnancy did not have any abnormal offspring. Liver Disease. CLOMID therapy is contraindicated in patients with liver disease or a history of liver dysfunction. Abnormal Uterine Bleeding. CLOMIDiscontraindicatedinpatientswithabnormaluterinebleedingofundetermined origin. Ovarian Cysts. CLOMID is contraindicated in patients with ovarian cysts or enlargement not due to polycystic ovarian syndrome. Other. CLOMIDiscontraindicated in patients with uncontrolled thyroid or adrenal dysfunction or in the presence of an organic intracranial lesion such as pituitary tumor . Additional information about Androxal Androxal Indication: Used mainly in female infertility due to anovulation(e.g.duetopolycysticovarysyndrome). In some countries, it is also registered for use in men. Mechanism Of Action: Androxal acts by inhibiting the action of estrogen on the gonadotrope cells in the anterior pituitary gland. "Sensing" low estrogen levels, follicle-stimulating hormone release is increased, leading to a higher rate of ovulation and hence pregnancy. Androxal hasnoapparentprogestational, androgenic, or antrandrogenic effects and does not appear to interfere with pituitary-adrenalorpituitary-thyroid function.Drug Interactions: Amobarbital The enzyme inducer decreases the effect of hormonesAprobarbital The enzyme inducer decreases the effect of hormonesButabarbital The enzyme inducer decreases the effect of hormonesButalbital The enzyme inducer decreases the effect of hormonesButethal The enzyme inducer decreases the effect of hormonesEthotoin The enzyme inducer decreases the effect of hormonesFosphenytoin TheenzymeinducerdecreasestheeffectofhormonesGriseofulvin The enzyme inducer decreases the effect of hormonesHeptabarbital TheenzymeinducerdecreasestheeffectofhormonesHexobarbitalTheenzymeinducerdecreasestheeffectofhormonesMephenytoin The enzyme inducer decreases the effect of hormonesMethohexital The enzyme inducer decreases the effect of hormonesMethylphenobarbital The enzyme inducer decreases the effect of hormonesPentobarbital The enzymeinducerdecreasestheeffectofhormonesPhenobarbital The enzyme inducer decreases the effect of hormonesPhenytoin The enzyme inducer decreases the effect of hormonesPrimidone The enzyme inducer decreases the effect of hormonesSecobarbital The enzyme inducer decreases the effect of hormonesTalbutal The enzyme inducer decreases theeffectofhormonesPrednisoloneTheestrogenicagentincreasestheeffectofcorticosteroidPrednisoneTheestrogenicagentincreases the effect of corticosteroidRaloxifene Association not recommendedUrsodeoxycholic acid Estrogens decreases the effect of ursodiolFood Interactions: Take without regard to meals.Generic Name: ClomifeneSynonyms: Clomifene citrate; Chloramiphene; Chloramifene; Chlomaphene; Cisclomiphene; Clomiphene Citrate; Clomifeno; Clomiphene citrate (Z,E); Clomiphene dihydrogen citrate; Racemic clomiphene citrate; Zuclomiphene citrateDrug Category: Estrogen Antagonists; Fertility Agents, Female; Selective Estrogen Receptor ModulatorsDrug Type: Small Molecule; Approved; InvestigationalOther Brand Names containing Clomifene: Clomid; Clomiphene; Clomiphene B; Clomivid; Clomphid; Clostilbegyt; Dyneric; Genozym; Ikaclomin; Milophene; Omifin; Serophene; Clomifert; Androxal; Absorption: Based on early studies with 14 C-labeled clomifene,thedrugwasshown to be readily absorbed orally in humans. Toxicity (Overdose): The acute oral LD50 of clomifene is 1700 mg/kg in mice and 5750 mg/kg in rats. The toxic dose in humans is not known. Toxic effects accompanying acute overdosageofclomifene have not been reported. Signs and symptoms of overdosageasaresultoftheuseofmorethantherecommended dose during clomifene therapy include nausea, vomiting, vasomotor flushes, visual blurring, spots or flashes, scotomata, ovarian enlargement with pelvic orabdominal pain. Protein Binding: Not AvailableBiotransformation: HepaticHalf Life: 5-7 daysDosage Forms of Androxal: Tablet OralChemical IUPAC Name: 2-[4-[(Z)-2-chloro-1,2-di(phenyl)ethenyl]phenoxy]-N,N-diethylethanamineChemical Formula: C26H28ClNO