indication

Used mainly in female infertility due to anovulation (e.g. due to polycystic ovary syndrome) to induce ovulation.

pharmacology

Clomifene (previously clomiphene) is an orally administered, non steroidal, ovulatory stimulant that acts as a selective estrogen receptor modulator (SERM). Clomifene can lead to multiple ovulation, and hence increase the risk of conceiving 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. Clomifene 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. Clomifene 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.

mechanism of action

Clomifene has both estrogenic and anti-estrogenic properties, but its precise mechanism of action has not been determined. Clomifene appears to stumulate the release of gonadotropins, follicle-stimulating hormone (FSH), and leuteinizing hormone (LH), which leads to the development and maturation of ovarian follicle, ovulation, and subsequent development and function of the coprus luteum, thus resulting in pregnancy. Gonadotropin release may result from direct stimulation of the hypothalamic-pituitary axis or from a decreased inhibitory influence of estrogens on the hypothalamic-pituitary axis by competing with the endogenous estrogens of the uterus, pituitary, or hypothalamus. Clomifene has no apparent progestational, androgenic, or antrandrogenic effects and does not appear to interfere with pituitary-adrenal or pituitary-thyroid function.

toxicity

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.

biotransformation

Hepatic

absorption

Based on early studies with 14 C-labeled clomifene, the drug was shown to be readily absorbed orally in humans.

half life

5-7 days

route of elimination

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. Mean urinary excretion was approximately 8% with fecal excretion of about 42%.

drug interactions

Amobarbital: The enzyme inducer, amobarbital, decreases the effect of the hormone agent, clomifene.

Aprobarbital: The enzyme inducer, aprobarbital, decreases the effect of the hormone agent, clomifene.

Butabarbital: The enzyme inducer, butabarbital, decreases the effect of the hormone agent, clomifene.

Butalbital: The enzyme inducer, butalbital, decreases the effect of the hormone agent, clomifene.

Butethal: The enzyme inducer, butethal, decreases the effect of the hormone agent, clomifene.

Ethotoin: The enzyme inducer, ethotoin, decreases the effect of the hormone agent, clomifene.

Fosphenytoin: The enzyme inducer, fosphenytoin, decreases the effect of the hormone agent, clomifene.

Griseofulvin: The enzyme inducer, griseofulvin, decreases the effect of the hormone agent, clomifene.

Heptabarbital: The enzyme inducer, heptabarbital, decreases the effect of the hormone agent, clomifene.

Hexobarbital: The enzyme inducer, hexobarbital, decreases the effect of the hormone agent, clomifene.

Mephenytoin: The enzyme inducer, mephenytoin, decreases the effect of the hormone agent, clomifene.

Methohexital: The enzyme inducer, methohexital, decreases the effect of the hormone agent, clomifene.

Methylphenobarbital: The enzyme inducer, methylphenobarbital, decreases the effect of the hormone agent, clomifene.

Pentobarbital: The enzyme inducer, pentobarbital, decreases the effect of the hormone agent, clomifene.

Phenobarbital: The enzyme inducer, phenobarbital, decreases the effect of the hormone agent, clomifene.

Phenytoin: The enzyme inducer, phenytoin, decreases the effect of the hormone agent, clomifene.

Prednisolone: The estrogenic agent, clomifene, may increase the effect of the corticosteroid, prednisolone.

Prednisone: The estrogenic agent, clomifene, may increase the effect of corticosteroid, prednisone.

Primidone: The enzyme inducer, primidone, decreases the effect of the hormone agent, clomifene.

Raloxifene: Association not recommended

Secobarbital: The enzyme inducer, secobarbital, decreases the effect of the hormone agent, clomifene.

Talbutal: The enzyme inducer, talbutal, decreases the effect of the hormone agent, clomifene.

Ursodeoxycholic acid: Estrogens decreases the effect of ursodiol