Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1422
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clomiphene citrate (Tablet)
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General Considerations: The workup and treatment of candidates for clomiphene citrate tablets USP therapy should be supervised by physicians experienced in management of gynecologic or endocrine disorders. Patients should be chosen for therapy with clomiphene citrate tablets USP only after careful diagnostic evaluation . The plan of therapy should be outlined in advance. Impediments to achieving the goal of therapy must be excluded or adequately treated before beginning clomiphene citrate tablets USP. The therapeutic objective should be balanced with potential risks and discussed with the patient and others involved in the achievement of a pregnancy. Ovulation most often occurs from 5 to 10 days after a course of clomiphene citrate tablets USP. Coitus should be timed to coincide with the expected time of ovulation. Appropriate tests to determine ovulation may be useful during this time.<br/>Recommended Dosage: Treatment of the selected patient should begin with a low dose, 50 mg daily (1 tablet) for 5 days. The dose should be increased only in those patients who do not ovulate in response to cyclic 50 mg clomiphene citrate tablets USP. A low dosage or duration of treatment course is particularly recommended if unusual sensitivity to pituitary gonadotropin is suspected, such as in patients with polycystic ovary syndrome . The patient should be evaluated carefully to exclude pregnancy, ovarian enlargement, or ovarian cyst formation between each treatment cycle. If progestin-induced bleeding is planned, or if spontaneous uterine bleeding occurs prior to therapy, the regimen of 50 mg daily for 5 days should be started on or about the 5th day of the cycle. Therapy may be started at any time in the patient who has had no recent uterine bleeding. When ovulation occurs at this dosage, there is no advantage to increasing the dose in subsequent cycles of treatment. If ovulation does not appear to occur after the first course of therapy, a second course of 100 mg daily (two 50 mg tablets given as a single daily dose) for 5 days should be given. This course may be started as early as 30 days after the previous one after precautions are taken to exclude the presence of pregnancy. Increasing the dosage or duration of therapy beyond 100 mg/day for 5 days is not recommended. The majority of patients who are going to ovulate will do so after the first course of therapy. If ovulation does not occur after three courses of therapy, further treatment with clomiphene citrate tablets USP is not recommended and the patient should be reevaluated. If three ovulatory responses occur, but pregnancy has not been achieved, further treatment is not recommended. If menses does not occur after an ovulatory response, the patient should be reevaluated. Long-term cyclic therapy is not recommended beyond a total of about 6 cycles .
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Clomiphene citrate tablets USP is an orally administered, nonsteroidal, ovulatory stimulant designated chemically as 2-[p-(2-chloro-1,2-diphenylvinyl)phenoxy] triethylamine citrate (1:1). It has the molecular formula of CHClNO���CHOand a molecular weight of 598.09. It is represented structurally as: Clomiphene citrate is a white to pale yellow, essentially odorless, crystalline powder. It is freely soluble in methanol; soluble in ethanol; slightly soluble in acetone, water, and chloroform; and insoluble in ether. Clomiphene citrate tablets USP is a mixture of two geometric isomers [cis (zuclomiphene) and trans (enclomiphene)] containing between 30% and 50% of the cis-isomer. Each white scored tablet contains 50 mg clomiphene citrate USP. The tablet also contains the following inactive ingredients: corn starch, lactose, magnesium stearate, pregelatinized corn starch, and sucrose.
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Action: Clomiphene citrate tablets USP is a drug of considerable pharmacologic potency. With careful selection and proper management of the patient, clomiphene citrate tablets USP has been demonstrated to be a useful therapy for the anovulatory patient desiring pregnancy. Clomiphene citrate 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. Clomiphene citrate 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 clomiphene 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. Available data suggest that both the estrogenic and antiestrogenic properties of clomiphene may participate in the initiation of ovulation. The two clomiphene isomers have been found to have mixed estrogenic and antiestrogenic effects, which may vary from one species to another. Some data suggest that zuclomiphene has greater estrogenic activity than enclomiphene. Clomiphene citrate has no apparent progestational, androgenic, or antiandrogenic effects and does not appear to interfere with pituitary-adrenal or pituitary-thyroid function. Although there is no evidence of a "carryover effect" of clomiphene citrate tablets USP, spontaneous ovulatory menses have been noted in some patients after clomiphene citrate tablets USP therapy.<br/>Pharmacokinetics: Based on early studies withC-labeled clomiphene citrate, the drug was shown to be readily absorbed orally in humans and excreted principally in the feces. Cumulative urinary and fecal excretion of theC averaged about 50% of the oral dose and 37% of an intravenous dose after 5 days. Mean urinary excretion was approximately 8% with fecal excretion of about 42%. SomeC label was still present in the feces 6 weeks after administration. Subsequent single-dose studies in normal volunteers showed that zuclomiphene (cis) has a longer half-life than enclomiphene (trans). Detectable levels of zuclomiphene persisted for longer than a month in these subjects. This may be suggestive of stereo-specific enterohepatic recycling or sequestering of the zuclomiphene. Thus, it is possible that some active drug may remain in the body during early pregnancy in women who conceive in the menstrual cycle during clomiphene citrate tablets USP therapy.<br/>CLINICAL STUDIES: During clinical investigations, 7578 patients received clomiphene citrate tablets USP, some of whom had impediments to ovulation other than ovulatory dysfunction . In those clinical trials, successful therapy characterized by pregnancy occurred in approximately 30% of these patients. There were a total of 2635 pregnancies reported during the clinical trial period. Of those pregnancies, information on outcome was only available for 2369 of the cases. Table 1 summarizes the outcome of these cases. Of the reported pregnancies, the incidence of multiple pregnancies was 7.98%: 6.9% twin, 0.5% triplet, 0.3% quadruplet, and 0.1% quintuplet. Of the 165 twin pregnancies for which sufficient information was available, the ratio of monozygotic to dizygotic twins was about 1:5. Table 1 reports the survival rate of the live multiple births. A sextuplet birth was reported after completion of original clinical studies; none of the sextuplets survived (each weighed less than 400 g), although each appeared grossly normal. The overall survival of infants from multiple pregnancies including spontaneous abortions, stillbirths, and neonatal deaths is 73%.
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Hypersensitivity: Clomiphene citrate tablets USP is contraindicated in patients with a known hypersensitivity or allergy to clomiphene citrate or to any of its ingredients.<br/>Pregnancy: Clomiphene citrate tablets USP should not be administered during pregnancy. Clomiphene citrate tablets USP may cause fetal harm in animals (see Animal Fetotoxicity). Although no causative evidence of a deleterious effect of clomiphene citrate tablets USP 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 clomiphene citrate tablets USP 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, ovarian enlargement, or ovarian cyst formation between each treatment cycle. The next course of clomiphene citrate tablets USP therapyshould be delayed until these conditions have been excluded.<br/>Fetal/Neonatal Anomalies and Mortality: The following fetal abnormalities have been reported subsequent to pregnancies following ovulation induction therapy with clomiphene citrate tablets USP during clinical trials. Each of the following fetal abnormalities were reported at a rate of<1% (experiences are listed in order of decreasing frequency): Congenital heart lesions, Down syndrome, club foot, congenital gut lesions, hypospadias, microcephaly, harelip and cleft palate, congenital hip, hemangioma, undescended testicles, polydactyly, conjoined twins and teratomatous malformation, patent ductus arteriosus, amaurosis, arteriovenous fistula, inguinal hernia, umbilical hernia, syndactyly, pectus excavatum, 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 clomiphene citrate tablets USP 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 clomiphene citrate tablets USP .<br/>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 abnormal reproductive 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.<br/>Liver Disease: Clomiphene citrate tablets USP therapy is contraindicated in patients with liver disease or a history of liver dysfunction .<br/>Abnormal Uterine Bleeding: Clomiphene citrate tablets USP is contraindicated in patients with abnormal uterine bleeding of undetermined origin .<br/>Ovarian Cysts: Clomiphene citrate tablets USP is contraindicated in patients with ovarian cysts or enlargement not due to polycystic ovarian syndrome .<br/>Other: Clomiphene citrate tablets USP is contraindicated in patients with uncontrolled thyroid or adrenal dysfunction or in the presence of an organic intracranial lesion such as pituitary tumor .
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50 mg tablets in cartons of 30 Tablets are round, white, scored, and debossed Watson over 781. Store tablets at controlled room temperature 59�����86��F (15�����30��C). Protect from heat, light, and excessive humidity, and store in closed containers.
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Signs and Symptoms: Toxic effects accompanying acute overdosage of clomiphene citrate tablets USP have not been reported. Signs and symptoms of overdosage as a result of the use of more than the recommended dose during clomiphene citrate tablets USP therapy include nausea, vomiting, vasomotor flushes, visual blurring, spots or flashes, scotomata, ovarian enlargement with pelvic or abdominal pain.<br/>Oral LD: The acute oral LDof clomiphene citrate tablets USP is 1700 mg/kg in mice and 5750 mg/kg in rats. The toxic dose in humans is not known.<br/>Dialysis: It is not known if clomiphene citrate tablets USP is dialyzable.<br/>Treatment: In the event of overdose, appropriate supportive measures should be employed in addition to gastrointestinal decontamination.
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clomiphene citrate
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clomiphene citrate (Tablet)
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Clinical Trial Adverse Events: Clomiphene citrate tablets USP, at recommended dosages, is generally well tolerated. Adverse reactions usually have been mild and transient and most have disappeared promptly after treatment has been discontinued. Adverse experiences reported in patients treated with clomiphene citrate during clinical studies are shown in Table 2. The following adverse events have been reported in fewer than 1% of patients in clinical trails: Acute abdomen, appetite increase, constipation, dermatitis or rash, depression, diarrhea, dizziness, fatigue, hair loss/dry hair, increased urinary frequency/volume, insomnia, light-headedness, nervous tension, vaginal dryness, vertigo, weight gain/loss. Patients on prolonged clomiphene citrate tablets USP therapy may show elevated serum levels of desmosterol. This is most likely due to a direct interference with cholesterol synthesis. However, the serum sterols in patients receiving the recommended dose of clomiphene citrate tablets USP are not significantly altered. Ovarian cancer has been infrequently reported in patients who have received fertility drugs. Infertility is a primary risk factor for ovarian cancer; however, epidemiology data suggest that prolonged use of clomiphene citrate tablets USP may increase the risk of a borderline or invasive ovarian tumor.<br/>Postmarketing Adverse Events: The following adverse experiences were reported spontaneously with clomiphene citrate tablets USP. The cause and effect relationship of the listed events to the administration of clomiphene citrate tablets USP is not known. Dermatologic: Acne, allergic reaction, erythema, erythema multiforme, erythema nodosum, hypertrichosis, pruritus Central Nervous System: Migraine headache, paresthesia, seizure, stroke, syncope Psychiatric: Anxiety, irritability, mood changes, psychosis Visual Disorders: Abnormal accommodation, cataract, eye pain, macular edema, optic neuritis, photopsia, posterior vitreous detachment, retinal hemorrhage, retinal thrombosis, retinal vascular spasm, temporary loss of vision Cardiovascular: Arrhythmia, chest pain, edema, hypertension, palpitation, phlebitis, pulmonary embolism, shortness of breath, tachycardia, thrombophlebitis Musculoskeletal: Arthralgia, back pain, myalgia Hepatic: Transaminases increased, hepatitis Neoplasms: Liver (hepatic hemangiosarcoma, liver cell adenoma, hepatocellular carcinoma); breast (fibrocystic disease, breast carcinoma); endometrium (endometrial carcinoma); nervous system (astrocytoma, pituitary tumor, prolactinoma, neurofibromatosis, glioblastoma multiforme, brain abcess); ovary (luteoma of pregnancy, dermoid cyst of the ovary, ovarian carcinoma); trophoblastic (hydatiform mole, choriocarcinoma); miscellaneous (melanoma, myeloma, perianal cysts, renal cell carcinoma, Hodgkin's lymphoma, tongue carcinoma, bladder carcinoma); and neoplasms of offspring (neuroectodermal tumor, thyroid tumor, hepatoblastoma, lymphocytic leukemia) Genitourinary: Endometriosis, ovarian cyst (ovarian enlargement or cysts could, as such, be complicated by adnexal torsion), ovarian hemorrhage, tubal pregnancy, uterine hemorrhage Body as a Whole: Fever, tinnitus, weakness Other: Leukocytosis, thyroid disorder<br/>Fetal/Neonatal Anomalies: The following fetal abnormalities have also been reported during postmarketing surveillance: delayed development; abnormal bone development including skeletal malformations of the skull, face, nasal passages, jaw, hand, limb (ectromelia including amelia, hemimelia, and phocomelia), foot, and joints; tissue malformations including imperforate anus, tracheoesophageal fistula, diaphragmatic hernia, renal agenesis and dysgenesis, and malformations of the eye and lens (cataract), ear, lung, heart (ventricular septal defect and tetralogy of Fallot), and genitalia; as well as dwarfism, deafness, mental retardation, chromosomal disorders, and neural tube defects (including anencephaly).
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Clomiphene citrate tablets USP is indicated for the treatment of ovulatory dysfunction in women desiring pregnancy. Impediments to achieving pregnancy must be excluded or adequately treated before beginning clomiphene citrate tablets USP therapy. Those patients most likely to achieve success with clomiphene therapy include patients with polycystic ovary syndrome , amenorrhea-galactorrhea syndrome, psychogenic amenorrhea, post-oral-contraceptive amenorrhea, and certain cases of secondary amenorrhea of undetermined etiology. Properly timed coitus in relationship to ovulation is important. A basal body temperature graph or other appropriate tests may help the patient and her physician determine if ovulation occurred. Once ovulation has been established, each course of clomiphene citrate tablets USP should be started on or about the 5th day of the cycle. Long-term cyclic therapy is not recommended beyond a total of about six cycles (including three ovulatory cycles). Clomiphene citrate tablets USP is indicated only in patients with demonstrated ovulatory dysfunction who meet the conditions described below : In addition, patients selected for clomiphene citrate tablets USP therapy should be evaluated in regard to the following: There are no adequate or well-controlled studies that demonstrate the effectiveness of clomiphene citrate tablets USP in the treatment of male infertility. In addition, testicular tumors and gynecomastia have been reported in males using clomiphene. The cause and effect relationship between reports of testicular tumors and the administration of clomiphene citrate tablets USP is not known. Although the medical literature suggests various methods, there is no universally accepted standard regimen for combined therapy (ie, clomiphene citrate tablets USP in conjunction with other ovulation-inducing drugs). Similarly, there is no standard clomiphene citrate tablets USP regimen for ovulation induction in in vitro fertilization programs to produce ova for fertilization and reintroduction. Therefore, clomiphene citrate tablets USP is not recommended for these uses.
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clomiphene citrate
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