Serophene (Clomiphene Citrate)

Serophene TABLETS (Serono)

DESCRIPTION

Each scored white tablet contains: clomiphene citrate, USP 50 mg. Clomiphene citrate is designated chemically as 2-[p-(2-chloro-1,2-diphenylvinyl) phenoxy] triethylamine dihydrogen citrate and is represented structurally as:

clomiphene citrate, USP (Serophene®)

As shown, one molecule of citric acid is chemically bound with one molecule of the organic base, clomiphene.

Clomiphene citrate is a chemical analog of other triarylethylene compounds such as chlorotrianisene and the cholesterol inhibitor, triparanol.

ACTIONS

Clomiphene citrate, an orally-administered, non-steroidal agent, may induce ovulation in selected anovulatory women. It is a drug of considerable pharmacologic potency. Careful evaluation and selection of the patient and close attention to the timing of the dose is mandatory prior to treatment with clomiphene citrate. Conservative selection and management of the patient contribute to successful therapy of anovulation. Clomiphene citrate induces ovulation in most selected anovulatory patients. The various criteria for ovulation include: an ovulation peak of estrogen excretion followed by a biphasic basal body temperature curve, urinary excretion of pregnanediol at post-ovulatory levels, and endometrial histologic findings characteristic of the luteal phase.

A review of eleven publications appearing between 1964 and 1978 showed that pregnancy occurred in 35% of 5,154 patients with ovulatory dysfunction who received clomiphene citrate.

Clomiphene citrate therapy appears to mediate ovulation through increased output of pituitary gonadotropins. These stimulate the maturation and endocrine activity of the ovarian follicle which is followed by the development and function of the corpus luteum. Increased urinary excretion of gonadotropins and estrogen suggests involvement of the pituitary.

Studies with 14 C labeled clomiphene citrate have shown that it is readily absorbed orally in humans and is excreted principally in the feces. An average of 51% of the administered dose was excreted after 5 days. After intravenous administration, 37% was excreted in 5 days. The appearance of 14 C in the feces six weeks after administration suggests that the remaining drug and/or metabolites are slowly excreted from a sequestered enterohepatic recirculation pool.

Indications And Clinical Uses:

Clomiphene citrate is indicated for the treatment of ovulatory failure in patients desiring pregnancy and whose husbands are fertile and potent. Impediments to this goal must be excluded or adequately treated before beginning therapy. Administration of clomiphene citrate is indicated only in patients with demonstrated ovulatory dysfunction and in whom the following conditions apply:

1. Normal liver function.

2. Physiologic indications of normal endogenous estrogen (as estimated from vaginal smears, endometrial biopsy, assay of serum [or urinary] estrogen, or from bleeding in response to progesterone). Reduced estrogen levels, while less favorable, do not prevent successful therapy.

3. Clomiphene citrate therapy is not effective for those patients with primary pituitary or ovarian failure. It cannot substitute for appropriate therapy of other disturbances leading to ovulatory dysfunction, e.g., diseases of the thyroid or adrenals.

4. Particularly careful evaluation prior to clomiphene citrate therapy should be done in patients with abnormal uterine bleeding. It is most important that neoplastic lesions are detected.

Contra-Indications:

Pregnancy:

Although no direct effect of clomiphene citrate therapy on the human fetus has been seen established, clomiphene citrate should not be administered in cases of suspected pregnancy as such effects have been reported in animals. To prevent inadvertent clomiphene citrate administration during early pregnancy, the basal body temperature should be recorded throughout all treatment cycles, and therapy should be discontinued if pregnancy is suspected. If the basal body temperature following clomiphene citrate is biphasic and is not followed by menses, the possibility of an ovarian cyst and/or pregnancy should be excluded. Until the correct diagnosis has been determined, the next course of therapy should be delayed.

Clomiphene citrate is also contraindicated in patients who have:

1. Uncontrolled thyroid or adrenal dysfunction.

2. An organic intracranial lesion such as a pituitary tumor.

3. Liver disease or a history of liver dysfunction.

4. Abnormal uterine bleeding of undetermined origin.

5. Ovarian cysts or enlargement not due to polycystic ovarian syndrome.

Manufacturers’ Warnings In Clinical States:

Visual Symptoms:

Patients should be warned that blurring and/or other visual symptoms may occur occasionally with clomiphene citrate therapy. These may make activities such as driving or operating machinery more hazardous than usual, particularly under conditions of variable lighting. While their significance is not yet understood (see “Adverse Reactions “), patients having any visual symptoms should discontinue treatment and have a complete ophthalmologic evaluation.

Ovarian Hyperstimulation Syndrome:

The Ovarian Hyperstimulation Syndrome (OHSS) has been reported to occur in patients receiving drug therapy for ovulation induction, including in rare cases patients receiving clomiphene citrate therapy. OHSS is a medical event distinct from uncomplicated ovarian enlargement. OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event. It is characterized by an apparent dramatic increase in vascular permeability which can result in a rapid accumulation of fluid in the peritoneal cavity, thorax, and potentially, the pericardium. The early warning signs of development of OHSS are severe pelvic pain, nausea, vomiting, and weight gain. The following symptomatology has been seen with cases of OHSS: abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting and diarrhea, severe ovarian enlargement, weight gain, dyspnea, and oliguria. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic phenomena. 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 the Ovarian Hyperstimulation Syndrome (OHSS).

Precautions:

Diagnosis Prior to Clomiphene Citrate Therapy:

Careful evaluation should be given to candidates for clomiphene citrate therapy. A complete pelvic examination should be performed prior to treatment and repeated before each subsequent course. Clomiphene citrate should not be given to patients with an ovarian cyst, as further ovarian enlargement may result.

Since the incidence of endometrial carcinoma and of ovulatory disorders increases with age, endometrial biopsy should always exclude the former as causative in such patients. If abnormal uterine bleeding is present, full diagnostic measures are necessary.

Ovarian Overstimulation During Treatment with Clomiphene Citrate:

To minimize the hazard associated with the occasional abnormal ovarian enlargement during clomiphene citrate therapy (see ” Adverse Reactions “), the lowest dose producing good results should be chosen. Some patients with polycystic ovarian syndrome are unusually sensitive to gonadotropins and may have an exaggerated response to usual doses of clomiphene citrate. Maximal enlargement of the ovary, whether abnormal or physiologic, does not occur until several days after discontinuation of clomiphene citrate. The patient complaining of pelvic pains after receiving clomiphene citrate should be examined carefully. If enlargement of the ovary occurs, clomiphene citrate therapy should be withheld until the ovaries have returned to pretreatment size, and the dosage or duration of the next course should be reduced. The ovarian enlargement and cyst formation following clomiphene citrate therapy regress spontaneously within a few days or weeks after discontinuing treatment. Therefore, unless a strong indication for laparoscopy (or laparotomy) exists, such cystic enlargement always should be managed conservatively.

Multiple Pregnancy:

In the reviewed publications, the incidence of multiple pregnancies was increased during those cycles in which clomiphene citrate was given. Among the 1,803 pregnancies on which the outcome was reported, 90% were single and 10% twins. Less than 1% of the reported deliveries resulted in triplets or more.

Of these multiple pregnancies, 96-99% resulted in the births of live infants. The patient and her husband should be advised of the frequency and potential hazards of multiple pregnancy before starting treatment.

Additional Precautions:

Prolonged use of clomiphene may increase the risk of a borderline or invasive ovarian tumor.

Adverse Reactions:

At the recommended dosage of clomiphene citrate, side effects occur infrequently and generally do not interfere with treatment. Adverse reactions tend to occur more frequently at higher doses and in the longer treatment courses used in some early studies.

The most frequent adverse reactions to clomiphene citrate include ovarian enlargement (approximately 1 in 7 patients), vasomotor flushes resembling menopausal symptoms which are not usually severe and promptly disappear after treatment is discontinued (approximately 1 in 10 patients), and abdominal discomfort (approximately 1 in 15 patients). Adverse reactions which occur less frequently (approximately 1 in 50 patients or more) include breast tenderness, nausea and vomiting, nervousness, insomnia, and visual disturbances. Other side effects which occur in less than 1 in 100 patients include headache, dizziness and light-headedness, increased urination, depression, fatigue, urticaria and allergic dermatitis, abnormal uterine bleeding, weight gain, ovarian cysts (ovarian enlargement or cysts could, as such, be complicated by adnexal torsion), and reversible hair loss.

Thromboembolic events, such as pulmonary embolism, arterial occlusion, and phlebitis, have been reported rarely in patients treated with clomiphene citrate. It is not clear what, if any, relationship these events have to clomiphene citrate therapy.

When clomiphene citrate is administered at the recommended dose, abnormal ovarian enlargement (see “Precautions”) is infrequent, although the usual cyclic variation in ovarian size may be exaggerated. Similarly, mid-cycle ovarian pain (mittelschmerz) may be accentuated.

With prolonged or higher dosage, ovarian enlargement and cyst formation (usually luteal) may occur more often, and the luteal phase of the cycle may be prolonged. Patients with polycystic ovarian syndrome may be unusually sensitive to clomiphene therapy. Rare occurrences of massive ovarian enlargement have been reported, for example, in a patient with polycystic ovarian syndrome whose clomiphene citrate therapy consisted of 100 mg daily for 14 days. Since abnormal ovarian enlargement usually regresses spontaneously, most of these patients should be treated conservatively. The Ovarian Hyperstimulation Syndrome has been reported to occur in rare cases in patients receiving clomiphene citrate therapy (see “Warnings”).

The incidence of visual symptoms (see “Warnings” for further recommendations), usually described as “blurring” or spots or flashes (scintillating scotomata), correlates with increasing total dose. Other visual symptoms which may occur include diplopia, phosphenes, photophobia, decreased visual acuity, loss of peripheral vision, and spatial distortion. The symptoms disappear usually within a few days or weeks after clomiphene citrate is discontinued. This may be due to intensification and/or prolongation of after-images. Symptoms often appear first, or are accentuated, upon exposure to a more brightly lit environment.

While measured visual acuity generally has not been affected, in one patient taking 200 mg daily, visual blurring developed on the seventh day of treatment and progressed to severe diminution of visual acuity by the tenth day. No other abnormality was coincident, and the visual acuity was normal by the third day after treatment was stopped. Ophthalmologically definable scotomata and electroretinographic retinal function changes have also been reported.

BSP Laboratory Studies:

Greater than 5% retention of sulfobromophthalein (BSP) has been reported in approximately 10% to 20% of patients in whom it was measured. Retention was usually minimal but was elevated during prolonged clomiphene citrate administration or with apparently unrelated liver disease. In some patients, pre-existing BSP retention decreased even though clomiphene citrate therapy was continued. Other liver function tests were usually normal.

Other Laboratory Studies:

Clomiphene citrate has not been reported to cause a significant abnormality in hematologic or renal tests, in protein bound iodine, or in serum cholesterol levels.

Birth Defects:

The following medical events have been reported subsequent to pregnancies following ovulation induction therapy with clomiphene citrate: ectopic pregnancy and congenital abnormalities such as syndactyly, polydactyly, congenital heart defects, retinal aplasia, hypospadias, ovarian dysplasia, cleft lip/palate, microencephaly and neural tube defects, including anencephaly. Some medical literature reports have implied an increased occurrence of neural tube defects, while others indicate that an increased incidence over that found in the general population does not exist. One case of a congenital abnormality (adactyly) in an infant exposed to clomiphene citrate in utero has been reported.

Of 1,803 births following clomiphene citrate administration, 45 infants with birth defects were reported for a cumulative rate of 2.5%.

Six cases of Down’ syndrome, one neonatal death with multiple malformations, and one case of each of the following were reported: club-foot, tibial torsion, blocked tear duct, and hemangioma. The other congenital abnormalities were not described. The investigators did not report that these were presumed to be due to therapy. The cumulative rate of congenital abnormalities does not exceed that reported in the general population.

Ovarian cancer has been reported in a very small number of infertile women who have been treated with clomiphene citrate. A causal relationship between treatment with clomiphene citrate and ovarian cancer has not been established.

Dosage And Administration:

General Considerations:

Physicians experienced in managing gynecologic or endocrine disorders should supervise the work-up and treatment of candidate patients for clomiphene citrate therapy. Patients should be chosen for clomiphene citrate therapy only after careful diagnostic evaluation (see “Indications”). 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.

In determining a starting dose schedule, efficacy must be balanced against potential side effects. For example, the available data so far suggest that ovulation and pregnancy are slightly more attainable with 100 mg/day for 5 days than with 50 mg/day for 5 days. As the dosage is increased, however, ovarian overstimulation and other side effects may be expected to increase. Although the data do not yet establish a relationship between dose level and multiple births, it is reasonable that such a correlation exists on pharmacologic grounds.

For these reasons, treatment of the usual patient should initiate with a 50 mg daily dose for 5 days. The dose may be increased only in those patients who do not respond to the first course (see “Recommended Dosage”). Special treatment with lower dosage over shorter duration is particularly recommended if unusual sensitivity to pituitary gonadotropin is suspected, including patients with polycystic ovarian syndrome (see “Precautions”).

Recommended Dosage:

The recommended dosage for the first course of clomiphene citrate is 50 mg (1 tablet) daily for 5 days. Therapy may be started at any time if the patient has had no recent uterine bleeding. If progestin-induced bleeding is intended, 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 fifth day of the cycle. 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 have occurred 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 may be started. This course may begin as early as 30 days after the previous one. It is recommended that the patient be examined for pregnancy, ovarian enlargement, or cyst formation between each treatment cycle. Increasing the dosage or duration of therapy beyond 100 mg/day for 5 days should not be undertaken.

The majority of patients who respond do so during the first course of therapy, and 3 courses constitute an adequate therapeutic trial. If ovulatory menses do not occur, the diagnosis should be re-evaluated. Treatment beyond this is not recommended in the patient who does not exhibit evidence of ovulation.

Pregnancy:

Properly timed coitus is very important for good results. For regularity of cyclic ovulatory response, it is also important that each course of clomiphene citrate be started on or about the fifth day of the cycle, once ovulation has been established. As with other therapeutic modalities, Serophene® therapy follows the rule of diminishing returns, such that the likelihood of conception diminishes with each succeeding course of therapy. If pregnancy has not been achieved after 3 ovulatory responses to Serophene®, further treatment generally is not recommended. Before starting treatment, patients should be advised of the possibility and potential hazards of multiple pregnancy if conception occurs following clomiphene citrate therapy.

Long-Term Cyclic Therapy – Not Recommended:

Since the relative safety of long-term cyclic therapy has not yet been demonstrated conclusively, and since the majority of patients will ovulate following 3 courses, long-term cyclic therapy is not recommended.

HOW SUPPLIED

Serophene® is available as 50 mg scored white tablets in the following package combinations:

1 carton 10 tablets, NDC 44087-8090-6

Each carton contains 2 strips of 5 tablets each.

1 carton 30 tablets, NDC 44087-8090-1

Each carton contains 3 strips of 10 tablets, each in a 2 — 5 arrangement.

Protect from light, moisture, and excessive heat. Dispense in well-closed, light resistant container as defined in the USP, with child resistant closure. Store at room temperature (15°-30°C/59°-86°F).

Caution: Federal law prohibits dispensing without prescription.

Serophene TABLETS (Serono)

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