Clomiphene Citrate

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Overview

What is Clomiphene Citrate?

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 C H ClNO • C H O and 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, which is the molar equivalent of 34 mg of the clomiphene base. The tablet also contains the following inactive ingredients: corn starch, lactose, magnesium stearate, pregelatinized corn starch, and sucrose.

What does Clomiphene Citrate look like?

What are the available doses of Clomiphene Citrate?

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What should I talk to my health care provider before I take Clomiphene Citrate?

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How should I use Clomiphene Citrate?

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 (see ), 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). (See and .)

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 fertilization programs to produce ova for fertilization and reintroduction. Therefore, clomiphene citrate tablets USP is not recommended for these uses.

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 (see ). 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.

What interacts with Clomiphene Citrate?

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What are the warnings of Clomiphene Citrate?

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Visual Symptoms

Patients should be advised that blurring or other visual symptoms such as spots or flashes (scintillating scotomata) may occasionally occur during therapy with clomiphene citrate tablets USP. These visual symptoms increase in incidence with increasing total dose or therapy duration. These visual disturbances are usually reversible; however, cases of prolonged visual disturbance have been reported with some occurring after clomiphene citrate tablets USP discontinuation. The visual disturbances may be irreversible, especially with increased dosage or duration of therapy. Patients should be warned that these visual symptoms may render such activities as driving a car or operating machinery more hazardous than usual, particularly under conditions of variable lighting.

These visual symptoms appear to be due to intensification and prolongation of afterimages. Symptoms often first appear or are accentuated with exposure to a brightly lit environment. While measured visual acuity usually has not been affected, a study patient taking 200 mg clomiphene citrate tablets USP daily developed visual blurring on the 7th day of treatment, which progressed to severe diminution of visual acuity by the 10th day. No other abnormality was found, and the visual acuity returned to normal on the 3rd day after treatment was stopped.

Ophthalmologically definable scotomata and retinal cell function (electroretinographic) changes have also been reported. A patient treated during clinical studies developed phosphenes and scotomata during prolonged clomiphene citrate tablets USP administration, which disappeared by the 32nd day after stopping therapy.

Postmarketing surveillance of adverse events has also revealed other visual signs and symptoms during clomiphene citrate tablets USP therapy (see ).

While the etiology of these visual symptoms is not yet understood, patients with any visual symptoms should discontinue treatment and have a complete ophthalmological evaluation carried out promptly.

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Ovarian Hyperstimulation Syndrome

The ovarian hyperstimulation syndrome (OHSS) has been reported to occur in patients receiving clomiphene citrate therapy for ovulation induction. OHSS may progress rapidly (within 24 hours to several days) and become a serious medical disorder. In some cases, OHSS occurred following cyclic use of clomiphene citrate therapy or when clomiphene citrate was used in combination with gonadotropins. Transient liver function test abnormalities suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver biopsy, have been reported in association with OHSS.

OHSS is a medical event distinct from uncomplicated ovarian enlargement. The clinical signs of this syndrome in severe cases can include gross ovarian enlargement, gastrointestinal symptoms, ascites, dyspnea, oliguria, and pleural effusion. In addition, the following symptoms have been reported in association with this syndrome: pericardial effusion, anasarca, hydrothorax, acute abdomen, hypotension, renal failure, pulmonary edema, intraperitoneal and ovarian hemorrhage, deep venous thrombosis, torsion of the ovary, and acute respiratory distress. The early warning signs of OHSS are abdominal pain and distention, nausea, vomiting, diarrhea, and weight gain. Elevated urinary steroid levels, varying degrees of electrolyte imbalance, hypovolemia, hemoconcentration, and hypoproteinemia may occur. Death due to hypovolemic shock, hemoconcentration, or thromboembolism has occurred. Due to fragility of enlarged ovaries in severe cases, abdominal and pelvic examination should be performed very cautiously. If conception results, rapid progression to the severe form of the syndrome may occur.

To minimize the hazard associated with occasional abnormal ovarian enlargement associated with clomiphene citrate tablets USP therapy, the lowest dose consistent with expected clinical results should be used. Maximal enlargement of the ovary, whether physiologic or abnormal, may not occur until several days after discontinuation of the recommended dose of clomiphene citrate tablets USP. Some patients with polycystic ovary syndrome who are unusually sensitive to gonadotropin may have an exaggerated response to usual doses of clomiphene citrate tablets USP. Therefore, patients with polycystic ovary syndrome should be started on the lowest recommended dose and shortest treatment duration for the first course of therapy (see ).

If enlargement of the ovary occurs, additional clomiphene citrate tablets USP therapy should not be given until the ovaries have returned to pretreatment size, and the dosage or duration of the next course should be reduced. Ovarian enlargement and cyst formation associated with clomiphene citrate tablets USP therapy usually regress spontaneously within a few days or weeks after discontinuing treatment. The potential benefit of subsequent clomiphene citrate tablets USP therapy in these cases should exceed the risk. Unless surgical indication for laparotomy exists, such cystic enlargement should always be managed conservatively.

A causal relationship between ovarian hyperstimulation and ovarian cancer has not been determined. However, because a correlation between ovarian cancer and nulliparity, infertility, and age has been suggested, if ovarian cysts do not regress spontaneously, a thorough evaluation should be performed to rule out the presence of ovarian neoplasia.

What are the precautions of Clomiphene Citrate?

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General

Careful attention should be given to the selection of candidates for clomiphene citrate tablets USP therapy. Pelvic examination is necessary prior to clomiphene citrate tablets USP treatment and before each subsequent course (see and ).

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Information for Patients

The 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:

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.

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Spontaneous Abortion and Congenital Anomalies:

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%. (See ). Among the birth anomalies spontaneously reported as individual cases since commercial availability of clomiphene citrate tablets USP, the proportion of neural tube defects has been high among pregnancies associated with ovulation induced by clomiphene citrate tablets USP, but this has not been supported by data from population-based studies.

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Drug Interactions

Drug interactions with clomiphene citrate tablets USP have not been documented.

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Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term toxicity studies in animals have not been performed to evaluate the carcinogenic or mutagenic potential of clomiphene citrate.

Oral administration of clomiphene citrate tablets USP to male rats at doses of 0.3 or 1 mg/kg/day caused decreased fertility, while higher doses caused temporary infertility. Oral doses of 0.1 mg/kg/day in female rats temporarily interrupted the normal cyclic vaginal smear pattern and prevented conception. Doses of 0.3 mg/kg/day slightly reduced the number of ovulated ova and corpora lutea, while 3 mg/kg/day inhibited ovulation.

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Pregnancy

Fetal Risk Summary

Clomiphene citrate use in pregnant women is contraindicated, as clomiphene citrate tablets USP treatment does not offer benefit in this population.

Available human data do not suggest an increased risk for congenital anomalies above the background population risk. However, animal reproductive toxicology studies showed increased embryo-fetal loss and structural malformations in offspring. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risks to the fetus.

Clinical Considerations

To avoid inadvertent clomiphene citrate tablets USP administration during early pregnancy, appropriate tests should be utilized during each treatment cycle to determine whether ovulation and/or pregnancy occurs. Patients should be evaluated carefully to exclude ovarian enlargement or ovarian cyst formation between each treatment cycle. The next course of clomiphene citrate USP therapy should be delayed until these conditions have been excluded.

Human data

The available human data from epidemiologic studies do not show any apparent cause and effect relationship between clomiphene citrate tablets USP periconceptual exposure and an increased risk of overall birth defects, or any specific anomaly. However, due to the small number of cases of congenital anomalies occurring in clomiphene citrate tablets USP treated women, these epidemiologic studies were only able to rule out large differences in risk. The studies did not consider factors associated with female subfertility and were unable to adjust for other important confounders.

In addition, available data do not support an increased rate of spontaneous abortion among subfertile women treated with clomiphene citrate for ovulation induction.

Animal data

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.

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Nursing Mothers

It is not known whether clomiphene citrate tablets USP is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if clomiphene citrate tablets USP is administered to a nursing woman. In some patients, clomiphene citrate tablets USP may reduce lactation.

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Ovarian Cancer

Prolonged use of clomiphene citrate tablets USP may increase the risk of a borderline or invasive ovarian tumor (see ).

What are the side effects of Clomiphene Citrate?

Clinical Trial Adverse Events.

Table 2

The following adverse events have been reported in fewer than 1% of patients in clinical trials: 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 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 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 may increase the risk of a borderline or invasive ovarian tumor.

**Table 2. Incidence of Adverse Events in Clinical Studies (Events Greater than 1%) (n = 8029*)**

POST MARKETING ADVERSE EVENTS

Abnormal bone development: skeletal malformations of the skull, face, nasal passages, jaw, hand, limb (ectromelia including amelia, hemimelia, and phocomelia),foot (clubfoot), spine and joints
Cardiac abnormalities: septal heart defects, muscular ventricular septal defect, patent ductus arteriosus, tetralogy of Fallot, and coarctation of the aorta
Chromosomal disorders:Downs syndrome
Ear abnormalities and deafness
Gastrointestinal tract abnormalities: cleft lip and palate, imperforate anus, tracheoesophageal fistula, diaphragmatic hernia, omphalocele
Genitalia abnormalities: hypospadias, cloacal exstrophy
Lung tissue malformations
Malformations of the eye and lens (cataract)
Neoplasms: neuroectodermal tumor, thyroid tumor, hepatoblastoma, lymphocytic, leukemia
Nervous system abnormalities: neural tube defects (anencephaly, meningomyelocele),microcephaly, and hydrocephalus
Renal abnormalities: renal agenesis and renal dysgenesis
Others: dwarfism, mental retardation

Postmarketing Adverse Events

The following adverse reactions have been identified during the post approval use of clomiphene citrate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole

Cardiovascular:

Central Nervous System

Dermatologic:

Fetal/Neonatal Anomalies:

Genitourinary:

Hepatic:

Musculoskeletal:

Neoplasms:

Psychiatric

Visual Disorders:

Other:

DRUGABUSE AND DEPENDENCE

Tolerance, abuse, or dependence with clomiphene citrate has not been reported.

What should I look out for while using Clomiphene Citrate?

What might happen if I take too much Clomiphene Citrate?

How should I store and handle Clomiphene Citrate?

Vials should be stored refrigerated at 2°-8°C (36°-46°F). Vials may be transferred to room temperature storage for a period not to exceed 2 months. Upon transfer, vial cartons must be marked by the dispensing pharmacist with a "DISCARD BY" date (2 months from the transfer date or the labeled expiration date, whichever comes first). Protect from light until administration.Vials should be stored refrigerated at 2°-8°C (36°-46°F). Vials may be transferred to room temperature storage for a period not to exceed 2 months. Upon transfer, vial cartons must be marked by the dispensing pharmacist with a "DISCARD BY" date (2 months from the transfer date or the labeled expiration date, whichever comes first). Protect from light until administration.NDC 43063-250-05: 50 mg Bottles of 5 tablets.Tablets are round, white, scored, and debossed over . Store tablets at controlled room temperature 59°-86°F (15°-30°C). Protect from heat, light, and excessive humidity, and store in closed containers.NDC 43063-250-05: 50 mg Bottles of 5 tablets.Tablets are round, white, scored, and debossed over . Store tablets at controlled room temperature 59°-86°F (15°-30°C). Protect from heat, light, and excessive humidity, and store in closed containers.NDC 43063-250-05: 50 mg Bottles of 5 tablets.Tablets are round, white, scored, and debossed over . 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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Clinical Information

Chemical Structure

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Clinical Pharmacology

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.

Non-Clinical Toxicology

Drug interactions with clomiphene citrate tablets USP have not been documented.

Careful attention should be given to the selection of candidates for clomiphene citrate tablets USP therapy. Pelvic examination is necessary prior to clomiphene citrate tablets USP treatment and before each subsequent course (see and ).

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Professional

Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

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Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).

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