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Questions & Answers
Side Effects & Adverse Reactions
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. These visual symptoms increase in incidence with increasing total dose or therapy duration and generally disappear within a few days or weeks after clomiPHENE citrate therapy is discontinued. However, prolonged visual disturbances have been reported after clomiPHENE citrate therapy has been discontinued and these disturbances may be irreversible. 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 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 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 therapy (see ADVERSE REACTIONS).
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.
Ovarian Hyperstimulation Syndrome
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. It may progress rapidly (within 24 hours to several days) to become a serious medical event. 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 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. Some patients with polycystic ovary syndrome who are unusually sensitive to gonadotropin may have an exaggerated response to usual doses of clomiPHENE citrate. 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 DOSAGE AND ADMINISTRATION).
If enlargement of the ovary occurs, additional clomiPHENE citrate 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 therapy usually regress spontaneously within a few days or weeks after discontinuing treatment. The potential benefit of subsequent clomiPHENE citrate 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.
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Serophene® (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 therapy. Those patients most likely to achieve success with clomiPHENE therapy include patients with polycystic ovary syndrome (see WARNINGS: Ovarian Hyperstimulation 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 therapy 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 DOSAGE AND ADMINISTRATION and PRECAUTIONS.)
Serophene® (clomiPHENE citrate tablets USP) is indicated only in patients with demonstrated ovulatory dysfunction who meet the conditions described below (see CONTRAINDICATIONS):
1. Patients who are not pregnant.
2. Patients without ovarian cysts. ClomiPHENE citrate should not be used in patients with ovarian enlargement except in those with polycystic ovary syndrome. Pelvic examination is necessary prior to the first and each subsequent course of clomiPHENE citrate treatment.
3. Patients without abnormal vaginal bleeding. If abnormal vaginal bleeding is present, the patient should be carefully evaluated to ensure that neoplastic lesions are not present.
4. Patients with normal liver function.
In addition, patients selected for clomiPHENE citrate therapy should be evaluated in regard to the following:
1. Estrogen Levels. Patients should have adequate levels of endogenous estrogen (as estimated from vaginal smears, endometrial biopsy, assay of urinary estrogen, or from bleeding in response to progesterone). Reduced estrogen levels, while less favorable, do not preclude successful therapy.
2. Primary Pituitary or Ovarian Failure. ClomiPHENE citrate therapy cannot be expected to substitute for specific treatment of other causes of ovulatory failure.
3. Endometriosis and Endometrial Carcinoma. The incidence of endometriosis and endometrial carcinoma increases with age as does the incidence of ovulatory disorders. Endometrial biopsy should always be performed prior to clomiPHENE citrate therapy in this population.
4. Other Impediments to Pregnancy. Impediments to pregnancy can include thyroid disorders, adrenal disorders, hyperprolactinemia, and male factor infertility.
5. Uterine Fibroids. Caution should be exercised when using clomiPHENE citrate in patients with uterine fibroids due to the potential for further enlargement of the fibroids.
There are no adequate and well-controlled studies that demonstrate the effectiveness of clomiPHENE citrate 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 is not known.
Although the medical literature suggests various methods, there is no universally accepted standard regimen for combined therapy (i.e., clomiPHENE citrate in conjunction with other ovulation-inducing drugs). Similarly, there is no standard clomiPHENE citrate regimen for ovulation induction in in vitro fertilization programs to produce ova for fertilization and reintroduction. Therefore, Serophene® is not recommended for these uses.
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ClomiPHENE citrate is an orally administered, nonsteroidal, ovulatory stimulant designated chemically as 2-[p-(2-chloro-1,2-diphenylvinyl) phenoxy] triethylamine citrate (1:1). It has a molecular formula of C26H28CINO ∙C6H8O7 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 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: lactose, microcrystalline cellulose, starch, colloidal silicon dioxide, magnesium stearate and sodium starch glycolate.