Clomid Information
Clomid (Clomiphene) Description
Clomid (Clomiphene) (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 • CHO 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.
Clomid (Clomiphene) 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 cornstarch, and sucrose.
Clomid (Clomiphene) Clinical Pharmacology
Clomid (Clomiphene) is a drug of considerable pharmacologic potency. With careful selection and proper management of the patient, Clomid (Clomiphene) 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 Clomid (Clomiphene) , spontaneous ovulatory menses have been noted in some patients after Clomid (Clomiphene) therapy.
Based on early studies with C-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 the C 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%.
Some C 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 Clomid (Clomiphene) therapy.
Clomid (Clomiphene) Clinical Studies
During clinical investigations, 7578 patients received Clomid (Clomiphene) , some of whom had impediments to ovulation other than ovulatory dysfunction (see ). 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%.
Clomid (Clomiphene) Indications And Usage
Clomid (Clomiphene) is indicated for the treatment of ovulatory dysfunction in women desiring pregnancy. Impediments to achieving pregnancy must be excluded or adequately treated before beginning Clomid (Clomiphene) 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 Clomid (Clomiphene) 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 .)
Clomid (Clomiphene) is indicated only in patients with demonstrated ovulatory dysfunction who meet the conditions described below (see ):
In addition, patients selected for Clomid (Clomiphene) therapy should be evaluated in regard to the following:
There are no adequate or well-controlled studies that demonstrate the effectiveness of Clomid (Clomiphene) 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 Clomid (Clomiphene) is not known.
Although the medical literature suggests various methods, there is no universally accepted standard regimen for combined therapy (ie, Clomid (Clomiphene) in conjunction with other ovulation-inducing drugs). Similarly, there is no standard Clomid (Clomiphene) regimen for ovulation induction in fertilization programs to produce ova for fertilization and reintroduction. Therefore, Clomid (Clomiphene) is not recommended for these uses.
Clomid (Clomiphene) Contraindications
Clomid (Clomiphene) should not be administered during pregnancy. Clomid (Clomiphene) may cause fetal harm in animals (see ). Although no causative evidence of a deleterious effect of Clomid (Clomiphene) 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 (see ).
To avoid inadvertent Clomid (Clomiphene) 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 Clomid (Clomiphene) therapy should be delayed until these conditions have been excluded.
Clomid (Clomiphene) Warnings
Patients should be advised that blurring or other visual symptoms such as spots or flashes (scintillating scotomata) may occasionally occur during therapy with Clomid (Clomiphene) . These visual symptoms increase in incidence with increasing total dose or therapy duration and generally disappear within a few days or weeks after Clomid (Clomiphene) is discontinued. 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 Clomid (Clomiphene) 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 Clomid (Clomiphene) administration, which disappeared by the 32nd day after stopping therapy.
Postmarketing surveillance of adverse events has also revealed other visual signs and symptoms during Clomid (Clomiphene) 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.
The ovarian hyperstimulation syndrome (OHSS) has been reported to occur in patients receiving clomiphene citrate therapy for ovulation induction. 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 ovarian hyperstimulation syndrome (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 Clomid (Clomiphene) 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 Clomid (Clomiphene) . Some patients with polycystic ovary syndrome who are unusually sensitive to gonadotropin may have an exaggerated response to usual doses of Clomid (Clomiphene) . 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 Clomid (Clomiphene) 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 Clomid (Clomiphene) therapy usually regresses spontaneously within a few days or weeks after discontinuing treatment. The potential benefit of subsequent Clomid (Clomiphene) 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.
Clomid (Clomiphene) Precautions
Long-term toxicity studies in animals have not been performed to evaluate the carcinogenic or mutagenic potential of clomiphene citrate.
Oral administration of Clomid (Clomiphene) 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.
Clomid (Clomiphene) Adverse Reactions
Clomid (Clomiphene) , 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 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 Clomid (Clomiphene) 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 Clomid (Clomiphene) 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.
The following adverse experiences were reported spontaneously with Clomid (Clomiphene) . The cause and effect relationship of the listed events to the administration of Clomid (Clomiphene) is not known.
Dermatologic:
Central Nervous System:
Psychiatric:
Visual Disorders:
Cardiovascular:
Musculoskeletal:
Hepatic:
Neoplasms:
Genitourinary:
Body as a Whole:
Other:
Clomid (Clomiphene) Drug Abuse And Dependence
Tolerance, abuse, or dependence with Clomid (Clomiphene) has not been reported.
Clomid (Clomiphene) Dosage And Administration
The workup and treatment of candidates for Clomid (Clomiphene) therapy should be supervised by physicians experienced in management of gynecologic or endocrine disorders. Patients should be chosen for therapy with Clomid (Clomiphene) 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 Clomid (Clomiphene) . 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 Clomid (Clomiphene) . Coitus should be timed to coincide with the expected time of ovulation. Appropriate tests to determine ovulation may be useful during this time.
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 Clomid (Clomiphene) . 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 (see ).
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 Clomid (Clomiphene) 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 six cycles (see ).
Clomid (Clomiphene) How Supplied
NDC 0068-0226-30: 50 mg tablets in cartons of 30
Tablets are round, white, scored, and debossed Clomid (Clomiphene) 50.
Store tablets at controlled room temperature 59–86°F (15–30°C). Protect from heat, light, and excessive humidity, and store in closed containers.
Clomid (Clomiphene)
