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 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.
Based on early studies with 14C-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 14C 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%.
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.
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.
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.
ClomiPHENE is contraindicated in patients with a known hypersensitivity or allergy to clomiPHENE citrate or to any of its ingredients.
ClomiPHENE should not be administered during pregnancy. ClomiPHENE citrate may cause fetal harm in animals (see Animal Fetotoxicity). Although no causative evidence of a deleterious effect of clomiPHENE citrate therapy on the human fetus has been established, there have been reports of birth anomalies which, during clinical studies, occurred at an incidence within the range reported for the general population (see Fetal/Neonatal Anomalies and Mortality; 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.
Careful attention should be given to the selection of candidates for clomiPHENE citrate therapy. Pelvic examination is necessary prior to clomiPHENE citrate treatment and before each subsequent course (see CONTRAINDICATIONS and WARNINGS).
Information for Patients
The purpose and risks of clomiPHENE citrate therapy should be presented to the patient before starting treatment. It should be emphasized that the goal of clomiPHENE citrate therapy is ovulation for subsequent pregnancy. The physician should counsel the patient with special regard to the following potential risks:
Visual Symptoms: Advise that blurring or other visual symptoms occasionally may occur during or shortly after clomiPHENE citrate therapy. It should be made clear that, in some instances, visual disturbances may be prolonged and, possibly, irreversible. Warn that visual symptoms may render such activities as driving a car or operating machinery more hazardous than usual, particularly under conditions of variable lighting (see WARNINGS).
Multiple Pregnancy: Inform the patient that there is an increased chance of multiple pregnancy, including bilateral tubal pregnancy and coexisting tubal and intrauterine pregnancy, when conception occurs in relation to clomiPHENE citrate therapy. The potential complications and hazards of multiple pregnancy should be explained.
Pregnancy Wastage and Birth Anomalies: The physician should explain the assumed risk of any pregnancy, whether ovulation is induced with the aid of clomiPHENE citrate or occurs naturally. The patient should be informed of the greater risks associated with certain characteristics or conditions of any pregnant woman, eg, age of female and male partner, history of spontaneous abortions, Rh genotype, abnormal menstrual history, infertility history, organic heart disease, diabetes, exposure to infectious agents such as rubella, familial history of birth anomaly, that may be pertinent to the patient for whom clomiPHENE citrate is being considered. Based upon the evaluation of the patient, genetic counseling may be indicated.
Long-term toxicity studies in animals have not been performed to evaluate the carcinogenic or mutagenic potential of clomiPHENE citrate.
Oral administration of clomiPHENE citrate to male rats at doses of 0.3 or 1 mg/kg/day caused decreased fertility,
Prolonged use of clomiPHENE citrate tablets USP may increase the risk of a borderline or invasive ovarian tumor (see ADVERSE REACTIONS).
Clinical Trial Adverse Events
ClomiPHENE citrate, at recommended dosages, is generally well tolerated. Adverse reactions usually have been mild and transient and most have disappeared promptly after treatment has been discontinued. Adverse experiences reported in patients treated with clomiPHENE citrate during clinical studies are shown in Table 2.
The following adverse events have been reported in fewer than 1% of patients in clinical trials: Acute abdomen, appetite increase, constipation, dermatitis or rash, depression, diarrhea, dizziness, fatigue, hair loss/dry hair, increased urinary frequency/volume, insomnia, light-headedness, nervous tension, vaginal dryness, vertigo, weight gain/loss.
Other: Leukocytosis, thyroid disorder
Fetal/Neonatal Anomalies: The following fetal abnormalities have also been reported during postmarketing surveillance: delayed development; abnormal bone development including skeletal malformations of the skull, face, nasal passages, jaw, hand, limb (ectromelia including amelia, hemimelia, and phocomelia), foot, and joints; tissue malformations including imperforate anus, tracheoesophageal fistula, diaphragmatic hernia, renal agenesis and dysgenesis, and malformations of the eye and lens (cataract), ear, lung, heart (ventricular septal defect and tetralogy of Fallot), and genitalia; as well as dwarfism, deafness, mental retardation, chromosomal disorders, and neural tube defects (including anencephaly).
DRUG ABUSE AND DEPENDENCE
Tolerance, abuse, or dependence with clomiPHENE citrate has not been reported.
Signs and Symptoms
Toxic effects accompanying acute overdosage of clomiPHENE citrate have not been reported. Signs and symptoms of overdosage as a result of the use of more than the recommended dose during clomiPHENE citrate therapy include nausea, vomiting, vasomotor flushes, visual blurring, spots or flashes, scotomata, ovarian enlargement with pelvic or abdominal pain. (See CONTRAINDICATIONS: Ovarian Cyst.)
In the event of overdose, appropriate supportive measures should be employed in addition to gastrointestinal decontamination.
The workup and treatment of candidates for clomiPHENE citrate therapy should be supervised by physicians experienced in management of gynecologic or endocrine disorders.
Treatment of the selected patient should begin with a low dose, 50 mg daily (1 tablet) for 5 days. The dose should be increased only in those patients who do not ovulate in response to cyclic 50 mg clomiPHENE citrate. A low dosage or duration of treatment course is particularly recommended if unusual sensitivity to pituitary gonadotropin is suspected, such as in patients with polycystic ovary syndrome (see WARNINGS: Ovarian Hyperstimulation Syndrome).