Serophene

SEROPHENE — clomiphene citrate tablet
EMD Serono, Inc.

DESCRIPTION

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 C26 H28 CINO ∙C6 H8 O7 and a molecular weight of 598.09. It is represented structurally as:

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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.

CLINICAL PHARMACOLOGY

Action

ClomiPHENE citrate is a drug of considerable pharmacologic potency. With careful selection and proper management of the patient, clomiPHENE citrate 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 citrate 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, spontaneous ovulatory menses have been noted in some patients after clomiPHENE citrate therapy.

Pharmacokinetics

Based on early studies with 14 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 14 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 14 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 clomiPHENE citrate therapy.

CLINICAL STUDIES

During clinical investigations, 7578 patients received clomiPHENE citrate, some of whom had impediments to ovulation other than ovulatory dysfunction (see INDICATIONS AND USAGE). 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.

Table 1 Outcome of Reported Pregnancies in Clinical Trials (n=2369)
Outcome Total Number of Pregnancies Survival Rate
* Includes 28 ectopic pregnancies, 4 hydatidiform moles, and 1 fetus papyraceous.
Indicates percentage of surviving infants from these pregnancies.
Pregnancy Wastage
Spontaneous Abortions 483*
Stillbirths 24
Live Births
Single Births 1697 98.16%
Multiple Births 165 83.25%

The overall survival of infants from multiple pregnancies including spontaneous abortions, stillbirths, and neonatal deaths is 73%.

INDICATIONS AND USAGE

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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