Serophene 50 mg

Information for the Patient

Serophene

Pharmacology

Serophene (clomiphene citrate) is an orally-administered, non-steroidal agent which may induce ovulation in anovulatory women in appropriately selected cases.

Mechanism of Action: The stimulation of an ovulatory response to cyclic clomiphene therapy is believed to be related to its antiestrogenic properties; by competing with estrogen for binding sites at the hypothalamic level, it may cause increased secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), with subsequent ovarian stimulation and preovulatory LH surge, resulting in maturation of the ovarian follicle and development of the corpus luteum.

The involvement of the pituitary is indicated by increased urinary excretion of gonadotropins and by the response of the ovary as manifested by increased urinary estrogen excretion.

Following therapy with clomiphene, presumptive signs of ovulation resemble those associated with normal menstrual cycle. It should be noted, however, that during drug administration and for several days thereafter, the effects of endogenous estrogen on the vaginal mucosa and cervical mucus are inhibited.

Suggested criteria for ovulation following clomiphene may include the ovulatory peak of estrogen excretion, a biphasic basal body temperature curve, urinary excretion of pregnanediol at post-ovulatory or higher levels, and endometrial histologic findings characteristic of the luteal phase. In most patients, ovulation appears to occur from 6 to 12 days after completion of therapy at recommended dosage.

A review of 14 publications appearing between 1964 and 1983 showed that an ovulatory response occurred in 74% of 8228 patients with ovulatory dysfunction who received clomiphene citrate. Successful therapy characterized by pregnancy occurred in 31% of the 8228 patients. (See Table 1.)

Indications

In the treatment of ovulatory failure in patients desiring pregnancy, whose partners have adequate sperm and who have potentially functional hypothalamic-hypophyseal ovarian systems and adequate endogenous estrogens. Impediments to this goal must be excluded or adequately treated before beginning therapy. The workup and treatment of candidates for clomiphene therapy should be supervised by physicians experienced in management of gynecologic or endocrine disorders. The workup of the patient must begin with a careful and detailed history of menstrual and reproductive function, and a complete physical examination. It should be followed by a selective and careful laboratory investigation, based on historical and physical findings.

The following considerations are appropriate for selection of patients: If any doubt exists as to the presence of early pregnancy, clomiphene therapy should be withheld until a diagnosis of pregnancy has been excluded. The partner's potential fertility and potency should be ascertained by semen analysis and other indicated examinations. Mechanical impediments to conception, such as tubal obstruction, should be excluded or adequately treated before undertaking therapy. The diagnosis of ovulatory dysfunction should be established by such standard techniques as basal body temperature curves, serial vaginal smears, cervical mucus, endometrial biopsy, and pregnanediol determination. Appropriate diagnostic measures should be undertaken to exclude primary pituitary failure or primary ovarian failure. Intact pituitary and ovaries are required for successful therapy. Ovulatory dysfunction in the presence of abnormally high levels of pituitary gonadotropins is indicative of ovarian failure, and patients in this category cannot be expected to respond to clomiphene. Adequacy of endogenous estrogen, as estimated by vaginal smears, cervical mucus, endometrial biopsy, or urinary estrogen determination, furnishes a measure of ovarian function and indirectly of pituitary function. Bleeding after progesterone administration (progesterone alone, not combined with estrogen) furnishes evidence of an adequate level of endogenous estrogen. A good level of endogenous estrogen provides a favorable prognosis for treatment. A reduced estrogen level, although less favorable does not always preclude successful therapy. Patients with abnormal or excessive bleeding should have particularly careful evaluation prior to therapy. It is most important to ensure that neoplastic lesions are not overlooked. Clinical evaluation of liver function should always precede therapy. When disorders such as diabetes, adrenal disease, or thyroid disease are identified during investigation, specific treatment should be undertaken and subfertility therapy reconsidered only after the underlying disorder has been adequately treated. Clomiphene cannot be expected to be a substitute for specific therapy of these conditions.

Precautions

Diagnosis prior to therapy: Careful attention should be given to diagnosis in candidates for clomiphene therapy. Complete pelvic examination including cervical cytology is mandatory prior to treatment, and pelvic examination should be repeated before each subsequent course. Clomiphene should not be given in the presence of an ovarian cyst, since further enlargement of the ovary may occur.

Patients in later reproductive life have a greater tendency to endometrial carcinoma as well as a higher incidence of anovulatory disorders. Dilation and curettage should always be done for diagnosis before starting Serophene therapy in such patients. If abnormal bleeding is present, full diagnostic measures are mandatory.

Overstimulation of the Ovary During Therapy: In order to minimize the hazard associated with the occasional abnormal ovarian enlargement associated with Serophene therapy (see Adverse Effects), the lowest dose consistent with expectation of good results should be used. The patient should be advised of the possibility of ovarian cyst formation and should be instructed to return for repeat pelvic examination between 2 and 3 weeks after starting each course of treatment. Some patients with polycystic ovarian syndrome who are unusually sensitive to gonadotropin may have an exaggerated response to usual doses of Serophene. It should be borne in mind that maximal enlargement of the ovary, whether physiologic or abnormal, does not occur until several days after discontinuation of the recommended dose of Serophene. The patient who complains of pelvic pain after receiving clomiphene should be examined with care. If enlargement of the ovary occurs, additional 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. Experience has shown that the ovarian enlargement and cyst formation associated with therapy regress spontaneously within a few days or weeks after discontinuing treatment. Unless surgical indication for laparotomy exists, such cystic enlargement should always be managed conservatively.

Multiple Pregnancy: The incidence of multiple pregnancy (including triplets, quadruplets and quintuplets) has been increased up to ten-fold when conception takes place during a cycle in which clomiphene citrate therapy is given. During clinical studies, 353 infants were born of 163 multiple pregnancies. Of these infants, 293 survived, including 27 of 62 infants from triplet, quadruplet and quintuplet pregnancies. The patient and her partner should be advised of the frequency and potential hazards of multiple pregnancy before starting treatment.

Diagnostic Interference: Plasma desmosterol concentrations (only with long-term use, possibly indicating interference with cholesterol synthesis), plasma transcortin concentrations, serum thyroxine concentrations, sex hormone-binding globulin concentrations, sulfobromophthalein (BSP) retention (indicating hepatotoxicity) and, thyroxine-binding globulin (TBG) concentrations (may be increased).

Carcinogenicity: Two cases of bilateral breast carcinoma in women treated with clomiphene have been reported.

Patient Check-ups: The following procedures may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition): Complete pelvic examination for evaluation of ovarian size (recommended prior to each course of treatment with clomiphene). Daily basal body temperature. Estrogen excretion determinations. Histological studies of luteal phase endometrium. Serum progesterone concentrations. Urinary excretion of pregnanediol (recommended during or after a cycle of clomiphene treatment to determine whether ovulation has occurred). Endometrial biopsy (recommended prior to initiation of clomiphene treatment in older patients to rule out the presence of endometrial carcinoma). Liver function tests (recommended prior to initiation of therapy with clomiphene). Ophthalmologic, including slit-lamp, examination (recommended if treatment with clomiphene is continued for more than 1 year).

Supplied

Each round, white, flat, beveled-edge scored tablet, identified S on one side, contains: clomiphene citrate USP 50 mg. Bottles of 50. Blister packs of 10. Store in well-closed containers between 15 to 30°C. Protect from light.

Contraindications

Pregnancy

Warnings

Visual symptoms: Patients should be advised that blurring or other visual symptoms, dizziness or light-headedness may occasionally occur during therapy with Serophene. Patients should be warned that visual symptoms may render such activities as driving a car or operating machinery more hazardous than usual, particularly under conditions of variable lighting. The significance of these visual symptoms is not yet understood (see Adverse Effects). If the patient has any visual symptoms, treatment should be discontinued and a complete ophthalmologic evaluation carried out.

Adverse Effects

Note: At recommended dosage, adverse effects are usually rare. Incidence and severity of adverse effects tend to be related to dose and duration of treatment and are usually reversible after clomiphene therapy is discontinued.

Use of clomiphene is associated with an increased incidence of multiple pregnancies and, therefore, possible premature deliveries.

Clomiphene may cause a decrease in cervical mucus which may interfere with response.

The following adverse effects have been selected on the basis of their potential clinical significance (possible cause in parenthesis where appropriate—not necessarily inclusive).

Those indicating need for medical attention: Incidence more frequent than 5%.

Abdominal discomfort (bloating, stomach or pelvic pain) may be most often related to ovulatory or premenstrual phenomena, to ovarian enlargement or to enlargement of fibroids.

At recommended dosage, abnormal ovarian enlargement (see Precautions) is infrequent, although the usual cyclic variations in ovarian size may be exaggerated. Similarly, cyclic ovarian pain (mittelschmerz) may be accentuated. With higher or prolonged dosage, more frequent ovarian enlargement and cyst formation (usually luteal) may occur, and the luteal phase of the cycle may be prolonged. Rare instances of massive ovarian enlargement are on record. Southam and Janovski described such an instance in a patient with polycystic ovary syndrome whose clomiphene citrate therapy consisted of 100 mg daily for 14 days. Abnormal ovarian enlargement usually regresses spontaneously, and while laparotomy was performed on several such patients, investigators believe most of these patients should have been treated conservatively.

Note: Maximum ovarian enlargement occurs several days after clomiphene therapy is discontinued.

Blurred vision (ocular toxicity): Visual symptoms (see Warnings for further recommendations) described usually as “blurring” or spots or flashes, disappear within a few days or weeks after clomiphene is discontinued. These symptoms appear to be due to intensification and prolongation of after-images. Symptoms often first appear or are accentuated with exposure to a more brightly lit environment. While measured visual acuity has not generally been affected, one patient taking 200 mg daily developed visual blurring on the seventh day of treatment, which progressed to severe diminution of visual acuity by the tenth day. No other abnormality was found and the visual acuity returned to normal on the third day after treatment was stopped. Another patient treated during clinical studies developed scotomata during prolonged administration, which disappeared on placebo. Monolateral exophthalmos associated with laboratory evidence of hyperthyroidism was observed in one patient concomitant with completion of the third course of clomiphene citrate. In a 34-year-old patient who had taken 3 courses of clomiphene citrate, slit-lamp microscopic examination showed a mild amount of posterior cortical subcapsular opacity in each eye. Ophthalmoscopic examination revealed normal findings. The ocular diagnosis was posterior cortical senile cataracts.

Yellowing of eyes and skin (hepatotoxicity).

Those indicating need for medical attention only if they continue or are bothersome: Incidence more frequent than 10%: Hot flashes: The vasomotor symptoms resemble long menopausal hot flashes, are not usually severe and disappear promptly after treatment is discontinued.

Incidence less frequent or rare: 1 to 2%.

Breast discomfort; dizziness or lightheadedness; headache; heavy menstrual periods or bleeding between periods; mental depression, nervousness, restlessness, sleeplessness, or tiredness; nausea or vomiting.

Other less frequently reported symptoms during therapy have included: urticaria or allergic dermatitis, weight gain, increased urinary frequency or volume, constipation or diarrhea. Moderate, reversible hair loss has been reported in a few patients, primarily on continuous therapy.

Clomiphene has not been reported to cause significant abnormality in the hematologic or renal systems, in protein-bound iodine, or in serum cholesterol. Analysis by gas liquid chromatography (GLC) of serum sterols from patients on prolonged, continuous administration of clomiphene yields a peak compatible with an elevated level of desmosterol. This peak is indicative of an interference with cholesterol synthesis. However, the serum sterol GLC pattern from patients receiving recommended doses of clomiphene is not significantly altered.

Sulfobromophthalein (BSP) retention of greater than 5% has been reported in 32 of 141 patients in whom it was measured, including 5 of 43 patients who received approximately the dose of clomiphene citrate now recommended. Retention was usually minimal unless associated with prolonged continuous 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. In a later study in which patients were given 6 consecutive monthly courses of clomiphene citrate (l00 mg daily for 3 days) or matching placebo, BSP tests were done on 94 patients. Values in excess of 5% retention were recorded in 11 patients, 6 of whom had received drug and 5 placebo. One patient developed jaundice on the nineteenth day of treatment (50 mg/day); liver biopsy revealed bile stasis without evidence of hepatitis. A male prison subject who received 200 mg daily for 77 days developed the clinical picture of infectious hepatitis; his cellmate was discovered to have had infectious hepatitis four months earlier.

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

Birth defects: From 2339 completed pregnancies associated with clomiphene administration, 58 birth defects have been reported, for a cumulative rate of 2.5%. They have been reported in 4 conceptions in the abortion/stillbirth category, 14 of 353 infants from multiple pregnancies, and 39 of 1676 infants from single pregnancies. Three live-born infants failed to survive.

Reported defects were congenital heart lesions (8 infants), Down's syndrome (5 infants), club foot (4 infants), congenital gut lesions (4 infants), hypospadias (3 infants), microcephaly (2 infants), harelip and cleft palate (2 infants), congenital hip (2 infants), polydactyly (both twins), conjoined twins with teratomatous malformation, patent ductus arteriosus, amaurosis (blindness), arteriovenous fistula, inguinal hernia, umbilical hernia, syndactyly, pectus excavatum, myopathy, dermoid cyst of scalp, omphalocele, spina bifida occulta, ichthyosis, persistent lingual frenulum, and 7 infants with multiple somatic defects.

Eight of the entire group of 58 infants were born to 7 of 153 mothers who received a course of clomiphene citrate during the first 6 weeks after conception.

An interval of 4, 4 and 10 months respectively elapsed between the last clomiphene citrate therapy and conception in 3 mothers. In a fourth mother, conception occurred during a subsequent ovulation induced by gonadotropin therapy.

The cumulative rate of congential abnormalities does not exceed that reported in the general population.

Overdose

Treatment

Dosage

Patients receiving clomiphene should be under supervision of a physician experienced in the treatment of gynecologic or endocrine disorders. Patients should be chosen for therapy with Serophene 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.

Patients who have been hypoestrogenic for prolonged periods may require pretreatment with estrogen to provide a more normal endometrium for ovum implantation. Estrogen therapy should be discontinued immediately before initiation of clomiphene citrate.

In some patients, a single injection of 5000 to 10 000 USP units of human chorionic gonadotropin (hCG) is given 3 to 7 days after the last dose of clomiphene to stimulate the midcycle LH surge which results in ovulation.

Many patients will respond to 50 mg clomiphene daily for 5 days (see Recommended Dosage). In the determination of a recommended starting dose schedule, efficacy must be balanced against potential side effects. For example, the data available so far suggest that ovulation and pregnancy are slightly more attainable on 100 mg/day for 5 days than on 50 mg/day for 5 days. As the dosage is increased, however, ovarian overstimulation and other side effects may be expected to increase. Furthermore, although the data does not yet establish a relationship between dosage and multiple births, it would seem reasonable on pharmacologic grounds that such a relationship does exist. For these reasons, it would seem prudent to begin the treatment of the usual patient with a lower dose, 50 mg daily for 5 days, and to increase the dose only in those patients who do not respond to the first course (see Recommended Dosage).

Patients with unusual sensitivity to pituitary gonadotropins (for example, those with polycystic ovarian syndrome) may require a lower dosage or shorter duration of clomiphene therapy. Use of clomiphene is not recommended in patients with ovarian cysts because further enlargement may occur. A patient's report of abdominal pain during clomiphene therapy indicates immediate pelvic examination. If ovarian enlargement or cyst formation has occurred, it is recommended that clomiphene therapy be withdrawn until the ovaries have returned to pretreatment size, usually within a few days or weeks. Dosage and duration of the next course of clomiphene should be reduced. If the patient receiving clomiphene experiences any visual disturbances, it is recommended that clomiphene therapy be withdrawn and a complete ophthalmologic examination performed. Ocular side effects usually disappear within a few days or weeks after the last dose of clomiphene.

The majority of patients who are going to respond will respond to the first course of therapy, and 3 courses should constitute an adequate therapeutic trial. Treatment beyond this is not recommended in the patient who does not exhibit evidence of ovulation. If ovulatory menses does not occur after 3 to 4 cycles of clomiphene therapy at the maximum dose, or pregnancy after a treatment-free interval of 3 to 6 months, the diagnosis should be re-evaluated.

Pregnancy: In most patients, ovulation appears to occur from 6 to 12 days after completion of therapy. For regularity of cyclic ovulatory response, it is also important that each course of clomiphene be started on or about the fifth cycle day, once ovulation has been established. The importance of properly timed coitus cannot be over-emphasized. Conception should be attempted by having intercourse every other day, starting within 48 hours before ovulation.

If a cycle of clomiphene is followed by a biphasic course of basal body temperature and menses do not ensue, the next cycle of clomiphene should be delayed until it is confirmed that the patient is not pregnant.

In common with other therapeutic modalities, therapy follows the rule of diminishing returns, such that likelihood of conception diminishes with each succeeding course of therapy. If pregnancy has not been achieved after 3 ovulatory responses, further treatment is not recommended. Patients should be advised of the possibility of multiple pregnancy and its potential hazards if conception occurs during a cycle in which clomiphene is given.

Recommended Dosage: Adults: Oral: 50 mg (1 tablet)/day for 5 days, starting on the fifth day of the menstrual cycle if bleeding occurs, or at any time in the patient who has had no recent uterine bleeding. If ovulation without conception occurs, this cycle is repeated until conception or for 3 or 4 cycles. When ovulation occurs at the regimen of 50 mg daily for 5 days, there is no advantage to increasing the dose in subsequent cycles of treatment. If ovulation does not occur, the dose is increased to 100 mg a day for 5 days (starting as early as 30 days after the previous course), repeated if ovulation without conception occurs. Some patients require up to 250 mg/day to induce ovulation.

Note: The majority of patients who are going to respond will respond to the first course of therapy, and 3 courses should constitute an adequate therapeutic trial. If ovulatory menses do not occur after 3 cycles of clomiphene therapy at the maximum dose, or pregnancy after a treatment-free interval of 3 to 6 months, the diagnosis should be re-evaluated. Treatment beyond this is not recommended in the patient who does not exhibit evidence of ovulation.

Usual adult prescribing limits: Doses over 100 mg/day for 5 days have been associated with a higher incidence of side effects, and patients receiving these doses should be carefully monitored.