Clomphid - General Information
A triphenyl ethylene stilbene derivative which is an estrogen agonist or antagonist depending on the target tissue.
Pharmacology of Clomphid
Clomphid (previously clomiphene) is an orally administered, non steroidal, ovulatory stimulant that acts as a selective estrogen receptor modulator (SERM). Clomphid can lead to multiple ovulation, and hence increasing the risk of twins. In comparison to purified FSH, the rate of ovarian hyperstimulation syndrome is low. There may be an increased risk of ovarian cancer, and weight gain. Clomphid 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. Clomphid 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 clomifene 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.
Clomphid for patients
The purpose and risks of clomiphene citrate tablets USP therapy should be presented to the patient before starting treatment. It should be emphasized that the goal of clomiphene citrate tablets USP 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 tablets USP therapy. 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.
The patient should be instructed to inform the physician whenever any unusual visual symptoms occur. If the patient has any visual symptoms, treatment should be discontinued and complete ophthalmologic evaluation performed.
Abdominal Pelvic Pain or Distention: Ovarian enlargement may occur during or shortly after therapy with clomiphene citrate tablets USP. To minimize the risks associated with ovarian enlargement, the patient should be instructed to inform the physician of any abdominal or elvic pain, weight gain, discomfort, or distention after taking clomiphene citrate tablets USP.
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 tablets USP 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 tablets USP 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 tablets USP is being considered. Based upon the evaluation of the patient, genetic counseling may be indicated.
The overall incidence of reported birth anomalies from pregnancies associated with maternal clomiphene citrate tablets USP ingestion during the investigational studies was within the range of that reported in published references for the general population.
During clinical investigation, the experience from patients with known pregnancy outcome (Table 1) shows a spontaneous abortion rate of 20.4% and stillbirth rate of 1.0%..
Drug interactions with clomiphene citrate tablets USP have not been documented.
CLOMID is contraindicated in patients with a known hypersensitivity or allergy to clomiphene citrate or to any of its ingredients.
CLOMID should not be administered during pregnancy. CLOMID may cause fetal harm in animals. Although no causative evidence of a deleterious effect of CLOMID 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. To avoid inadvertent CLOMID administration during early pregnancy, appropriate tests should be utilized during each treatment cycle to determine whether ovulation occurs. The patient should be evaluated carefully to exclude pregnancy, ovarian enlargement, or ovarian cyst formation between each treatment cycle. The next course of CLOMID therapy should be delayed until these conditions have been excluded.
Fetal/Neonatal Anomalies and Mortality. The following fetal abnormalities have been reported subsequent to pregnancies following ovulation induction therapy with CLOMID during clinical trials. Each of the following fetal abnormalities were reported at a rate of < 1% (experiences are listed in order of decreasing frequency): Congenital heart lesions, Down syndrome, club foot, congenital gut lesions, hypospadias, microcephaly, harelip and cleft palate, congenital hip, hemangioma, undescended testicles, polydactyly, conjoined twins and teratomatous malformation, patent ductus arteriosus, amaurosis, arteriovenous fistula, inguinal hernia, umbilical hernia, syndactyly, pectus excavatum, myopathy, dermoid cyst of scalp, omphalocele, spina bifida occulta, ichthyosis, and persistent lingual frenulum. Neonatal death and fetal death/stillbirth in infants with birth defects have also been reported at a rate of < 1%. The overall incidence of reported birth anomalies from pregnancies associated with maternal CLOMID ingestion during clinical studies was within the range of that reported for the general population.
In addition, reports of birth anomalies have been received during postmarketing surveillance of CLOMID.
Animal Fetotoxicity. Oral administration of clomiphene citrate to pregnant rats during organogenesis at doses of 1 to 2 mg/kg/day resulted in hydramnion and weak, edematous fetuses with wavy ribs and other temporary bone changes. Doses of 8 mg/kg/day or more also caused increased resorptions and dead fetuses, dystocia, and delayed parturition, and 40 mg/kg/day resulted in increased maternal mortality. Single doses of 50 mg/kg caused fetal cataracts, while 200 mg/kg caused cleft palate.
Following injection of clomiphene citrate 2 mg/kg to mice and rats during pregnancy, the offspring exhibited metaplastic changes of the reproductive tract. Newborn mice and rats injected during the first few days of life also developed metaplastic changes in uterine and vaginal mucosa, as well as premature vaginal opening and anovulatory ovaries. These findings are similar to the abnormal reproductive behavior and sterility described with other estrogens and antiestrogens.
In rabbits, some temporary bone alterations were seen in fetuses from dams given oral doses of 20 or 40 mg/kg/day during pregnancy, but not following 8 mg/kg/day. No permanent malformations were observed in those studies. Also, rhesus monkeys given oral doses of 1.5 to 4.5 mg/kg/day for various periods during pregnancy did not have any abnormal offspring.
Liver Disease. CLOMID therapy is contraindicated in patients with liver disease or a history of liver dysfunction.
Abnormal Uterine Bleeding. CLOMID is contraindicated in patients with abnormal uterine bleeding of undetermined origin.
Ovarian Cysts. CLOMID is contraindicated in patients with ovarian cysts or enlargement not due to polycystic ovarian syndrome. Other. CLOMID is contraindicated in patients with uncontrolled thyroid or adrenal dysfunction or in the presence of an organic intracranial lesion such as pituitary tumor.
Additional information about Clomphid
Clomphid Indication: Used mainly in female infertility due to anovulation (e.g. due to polycystic ovary syndrome). In some countries, it is also registered for use in men.
Mechanism Of Action: Clomphid acts by inhibiting the action of estrogen on the gonadotrope cells in the anterior pituitary gland. "Sensing" low estrogen levels, follicle-stimulating hormone release is increased, leading to a higher rate of ovulation and hence pregnancy. Clomphid has no apparent progestational, androgenic, or antrandrogenic effects and does not appear to interfere with pituitary-adrenal or pituitary-thyroid function.
Drug Interactions: Amobarbital The enzyme inducer decreases the effect of hormones
Aprobarbital The enzyme inducer decreases the effect of hormones
Butabarbital The enzyme inducer decreases the effect of hormones
Butalbital The enzyme inducer decreases the effect of hormones
Butethal The enzyme inducer decreases the effect of hormones
Ethotoin The enzyme inducer decreases the effect of hormones
Fosphenytoin The enzyme inducer decreases the effect of hormones
Griseofulvin The enzyme inducer decreases the effect of hormones
Heptabarbital The enzyme inducer decreases the effect of hormones
Hexobarbital The enzyme inducer decreases the effect of hormones
Mephenytoin The enzyme inducer decreases the effect of hormones
Methohexital The enzyme inducer decreases the effect of hormones
Methylphenobarbital The enzyme inducer decreases the effect of hormones
Pentobarbital The enzyme inducer decreases the effect of hormones
Phenobarbital The enzyme inducer decreases the effect of hormones
Phenytoin The enzyme inducer decreases the effect of hormones
Primidone The enzyme inducer decreases the effect of hormones
Secobarbital The enzyme inducer decreases the effect of hormones
Talbutal The enzyme inducer decreases the effect of hormones
Prednisolone The estrogenic agent increases the effect of corticosteroid
Prednisone The estrogenic agent increases the effect of corticosteroid
Raloxifene Association not recommended
Ursodeoxycholic acid Estrogens decreases the effect of ursodiol
Food Interactions: Take without regard to meals.
Generic Name: Clomifene
Synonyms: Clomifene citrate; Chloramiphene; Chloramifene; Chlomaphene; Cisclomiphene; Clomiphene Citrate; Clomifeno; Clomiphene citrate (Z,E); Clomiphene dihydrogen citrate; Racemic clomiphene citrate; Zuclomiphene citrate
Drug Category: Estrogen Antagonists; Fertility Agents, Female; Selective Estrogen Receptor Modulators
Drug Type: Small Molecule; Approved; Investigational
Absorption: Based on early studies with 14 C-labeled clomifene, the drug was shown to be readily absorbed orally in humans.
Toxicity (Overdose): The acute oral LD50 of clomifene is 1700 mg/kg in mice and 5750 mg/kg in rats. The toxic dose in humans is not known. Toxic effects accompanying acute overdosage of clomifene have not been reported. Signs and symptoms of overdosage as a result of the use of more than the recommended dose during clomifene therapy include nausea, vomiting, vasomotor flushes, visual blurring, spots or flashes, scotomata, ovarian enlargement with pelvic or abdominal pain.
Protein Binding: Not Available
Half Life: 5-7 days
Dosage Forms of Clomphid: Tablet Oral
Chemical IUPAC Name: 2-[4-[(Z)-2-chloro-1,2-di(phenyl)ethenyl]phenoxy]-N,N-diethylethanamine
Chemical Formula: C26H28ClNO
Clomifene on Wikipedia: https://en.wikipedia.org/wiki/Clomifene
Organisms Affected: Humans and other mammals