Hoechst Marion Roussel
Action And Clinical Pharmacology: Clomiphene is an orally-administered, nonsteroidal agent which may induce ovulation in anovulatory women in appropriately selected cases. The ovulatory response to cyclic clomiphene therapy appears to be mediated through increased output of pituitary gonadotropins, which in turn stimulate the maturation and endocrine activity of the ovarian follicle and the subsequent development and function of the corpus luteum. The role 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. Antagonism of competitive inhibition of endogenous estrogen may play a role in the action of clomiphene on the pituitary.
Clomiphene is a drug of considerable pharmacologic potency. Its administration should be preceded by careful evaluation and selection of the patient, and must be accompanied by close attention to the timing of the dose. With conservative selection and management of the patient, clomiphene has been demonstrated to be a useful therapy for the anovulatory patient.
Based on studies with C-14 labelled clomiphene, the drug is readily absorbed orally in humans, and is excreted principally in the feces. Excretion of C-14 averaged 51% of the dose after 5 days in 6 subjects given clomiphene C-14. After i.v. administration, 37% was excreted in 5 days. Since C-14 appeared in the feces 6 weeks after administration, available data suggested that the remaining drug/metabolites were being slowly excreted from a sequestered enterohepatic recirculation pool.
Indications And Clinical Uses: For induction of ovulation in patients with persistent ovulatory dysfunction who desire pregnancy. The work-up and treatment of candidates for clomiphene therapy should be supervised by physicians experienced in management of gynecologic or endocrine disorders. Patients should be chosen for therapy with clomiphene only after careful diagnostic evaluation. The work-up 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: 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 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 with clomiphene. A reduced estrogen level, although less favorable, does not always preclude successful therapy.
Mechanical impediments to conception, such as tubal obstruction, should be excluded or adequately treated, before undertaking clomiphene therapy.
When disorders such as diabetes, adrenal disease, or thyroid disease are identified during the investigation, specific treatment should be undertaken and subfertility therapy reconsidered only after the underlying disorder has been adequately treated. Clomiphene cannot be expected to substitute for specific therapy of these conditions.
The husband’s potential fertility should be ascertained by semen analysis and other indicated examination.
Patients with abnormal or excessive bleeding should have particularly careful evaluation prior to clomiphene therapy. It is most important to ensure that neoplastic lesions are not overlooked.
Clinical evaluation of liver function should always precede clomiphene therapy.
Contra-Indications: Pregnancy: Although no causative evidence of a deleterious effect of clomiphene therapy on the human fetus has been seen, such evidence in regard to the rat and the rabbit has been presented. Therefore, clomiphene should not be administered during pregnancy. To avoid inadvertent clomiphene administration during early pregnancy, careful pelvis examination must be done prior to each course of therapy, the basal body temperature must be recorded throughout all treatment cycles, and the patient should be carefully observed to determine whether ovulation occurs. If the basal body temperature following clomiphene is biphasic and is not followed by menses, the patient should be examined carefully for the presence of an ovarian cyst and should have a pregnancy test. The next course of therapy should be delayed until the possibility of pregnancy has been excluded.
Liver Disease: Clomiphene therapy is contraindicated in patients with liver disease or a liver dysfunction.
Abnormal bleeding: Clomiphene is contraindicated in patients with abnormal bleeding of undetermined origin. Clomiphene is not indicated for the management of menstrual disorders.
Manufacturers’ Warnings In Clinical States: Visual Symptoms: Patients should be advised that blurring or other visual symptoms may occasionally occur during therapy with clomiphene. 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 complete ophthalmologic evaluation carried out.
Precautions: Diagnosis Prior to Clomiphene 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. Dilatation and curettage should always be done for diagnosis before starting clomiphene therapy in such patients. If abnormal bleeding is present, full diagnostic measures are mandatory.
Overstimulation of the Ovary During Clomiphene Therapy: In order to minimize the hazard associated with the occasional abnormal ovarian enlargement associated with clomiphene 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 ovary syndrome who are unusually sensitive to gonadotropin may have an exaggerated response to usual doses of clomiphene. 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 clomiphene. 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 clomiphene 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 tenfold when conception takes place during a cycle in which clomiphene 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 husband should be advised of the frequency and potential hazards of multiple pregnancy before starting treatment.
Adverse Reactions: At recommended dosage, side effects are not prominent and infrequently interfere with treatment. Side effects tend to be dose related, occurring more frequently at the higher doses and longer duration of treatment courses used in some earlier studies. The more common side effects include hot flashes, abdominal discomfort (distention, bloating, pain, or soreness), ovarian enlargement, and visual blurring.
The vasomotor symptoms resembling menopausal “hot flashes” are not usually severe and disappear promptly after treatment is discontinued. Abdominal symptoms may be most often related to ovulatory (mittelschmerz) or premenstrual phenomena, or to ovarian enlargement. Nausea, and rarely vomiting, constipation or diarrhea have been described less often.
At recommended dosage, abnormal ovarian enlargement (see also Precautions) is infrequent, although the usual cyclic variation 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 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.
Visual symptoms (see also 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 clomiphene administration, which disappeared on placebo. Monolateral exophthalmos associated with laboratory evidence of hyperthyroidism was observed in 1 patient concomitant with completion of the third course of clomiphene.
In a 34-year-old patient who had taken 3 courses of clomiphene, 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.
Other less frequently reported symptoms during therapy have included nausea or vomiting, increased nervous tension, depression, fatigue, dizziness or lightheadedness, insomnia, headache, breast soreness, heavier menses, intermenstrual spotting, urticaria or allergic dermatitis, weight gain, and increased urinary frequency or volume. Moderate, reversible hair loss has been reported in a few patients, primarily on prolonged 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 now recommended. Retention was usually minimal unless associated with prolonged continuous clomiphene administration or with apparently unrelated liver disease. In some patients, pre-existing BSP retention decreased even though clomiphene 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 (100 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 4 months earlier.
Birth Defects: From 2 339 completed pregnancies associated with clomiphene administration, 58 birth defects have been reported. They have been reported in 4 conceptions in the abortion/stillbirth category, 14 of 353 infants from multiple pregnancies, and 39 of 1 676 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), hemangioma (2 infants), undescended testes (2 infants), polydactyly (both of 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, icthyosis, 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 during the first 6 weeks after conception.
An interval of 4, 4, and 10 months respectively elapsed between the last clomiphene therapy and conception in 3 mothers. In a 4th mother conception occurred during a subsequent ovulation induced by gonadotropin therapy.
Ovarian Cancer: 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.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no known antidote but gastric lavage should be performed. tag_DosageDosage
Dosage And Administration: General Considerations: The work-up and treatment of candidates for clomiphene therapy should be supervised by physicians experienced in management of gynecologic or endocrine disorders. Patients should be chosen for therapy with clomiphene 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. Many patients will respond to 50 mg 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 do 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). Special care in dosage is particularly recommended if unusual sensitivity to pituitary gonadotropin is suspected, such as in patients with polycystic ovary syndrome.
Recommended Dosage: The recommended dose for the first course of clomiphene is 50 mg (1 tablet) daily for 5 days. Therapy may be started at any time in the patient who has had no recent uterine bleeding. 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 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 appears not to have occurred after the first course of therapy, a second course of 100 mg (two 50 mg tablets) daily 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. Increasing the dosage or duration of therapy beyond 100 mg/day for 5 days should never be undertaken.
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 have not yet occurred, the diagnosis should be re-evaluated. Treatment beyond this is not recommended in the patient who does not exhibit evidence of ovulation.
Pregnancy: The importance of properly timed coitus cannot be over-emphasized. 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. In common with other therapeutic modalities, clomiphene 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 to clomiphene, 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.
Long-term Cyclic Therapy Not Recommended: Since the relative safety of long-term cyclic therapy has not yet been conclusively demonstrated, and since the majority of patients will ovulate following 3 courses, long-term cyclic therapy is not recommended.
Availability And Storage: Each white scored tablet contains: clomiphene citrate USP 50 mg. Nonmedicinal ingredients: cornstarch, lactose, magnesium stearate and sucrose. Energy: 4.5 kJ (1.1 kcal)/tablet. Bottles of 50. Protect from light and moisture. (Shown in Product Recognition Section)
CLOMID® Hoechst Marion Roussel Clomiphene Citrate Ovulatory Agent