Clomiphene

Clomiphene is an Ovulation Stimulator belonging to the pharmacology class of Selective Estrogen Receptor Modulator.

Clomiphene can be used in the treatment of ovulatory dysfunction

Clomiphene is Readily absorbed from the gastrointestinal tract. Time to peak plasma concentration: Approx 6 hours and get metabolized in the liver; undergoes enterohepatic recirculation and get excreted mainly via faeces (42%); urine (8%) with elimination half-life: Approx 5 days.

The common side effects of Clomiphene includes: Ovarian hyperstimulation syndrome (OHSS), ovarian enlargement and cyst formation (high doses or prolonged treatment), visual disturbances (e.g. blurred vision, scintillating scotomata, phosphenes), multiple or ectopic pregnancy, new-onset or exacerbation .

Clomiphene is available in the form of Tablets.

The molecule is available in India, Japan, Germany, China.

Clomiphene is a nonsteroidal compound with both estrogenic and anti-estrogenic effects. Its exact mechanism of action in inducing ovulation has not been determined; however, it appears to stimulate the release of pituitary gonadotropic hormones probably by inhibiting the negative feedback effect of estrogens at the receptor sites in the hypothalamus and pituitary.

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.

Clomiphene is approved for use in the following clinical indications:

Treatment of ovulatory dysfunction: Treatment of ovulatory dysfunction in patients desiring to become pregnant.

Ovulation induction:

Time intercourse to coincide with the expected time of ovulation (usually 5 to 10 days after a clomiphene course).

Initial course:

Oral: 50 mg once daily for 5 days. Begin on or about the fifth day of cycle if progestin-induced bleeding is scheduled or spontaneous uterine bleeding occurs prior to therapy. Therapy may be initiated at any time in patients with no recent uterine bleeding.

Dose adjustment:

Oral: Subsequent doses may be increased to 100 mg once daily for 5 days only if ovulation does not occur at the initial dose. A lower dose of 25 mg may be used in patients sensitive to clomiphene or who consistently develop large ovarian cysts.

Repeat courses: If needed, the 5-day cycle may be repeated as early as 30 days after the previous one. Exclude the presence of pregnancy. The lowest effective dose should be used.

Maximum dose/duration of therapy:

• Tablets:50 mg

Tablets

Clomiphene may be contraindicated in the following conditions:

Hypersensitivity to clomiphene citrate or any of its components; liver disease or history of liver disease; abnormal uterine bleeding; enlargement or development of ovarian cyst (not due to polycystic ovarian syndrome); uncontrolled thyroid or adrenal dysfunction; presence of an organic intracranial lesion such as pituitary tumor; pregnancy.

Concerns related to adverse effects:

Hyperlipidemia: Patients with, or a family history of, hyperlipidemia may be at increased risk of hypertriglyceridemia. High doses of clomiphene or long durations of therapy may increase risk this risk. Pancreatitis has been reported. Pretreatment screening of triglycerides is recommended.

Ovarian enlargement: May be accompanied by abdominal distention or abdominal pain and generally regresses without treatment within a few days or weeks after therapy discontinuation. If ovaries are abnormally enlarged, withhold therapy until ovaries return to pretreatment size; reduce clomiphene dose and duration of future cycles.

Ovarian hyperstimulation syndrome: Ovarian hyperstimulation syndrome (OHSS) is a rare, exaggerated response to ovulation induction therapy. This syndrome may begin within 24 hours of human chorionic gonadotropin treatment but may become most severe 7 to 10 days after therapy. Mild/moderate OHSS signs/symptoms may include abdominal distention/discomfort, diarrhea, nausea, vomiting, and mild/moderate enlargement of ovaries/ovarian cysts. Severe OHSS signs/symptoms may include severe abdominal pain, anuria/oliguria, ascites, severe dyspnea, hypotension, hydrothorax, nausea/vomiting (intractable), pleural effusion, rapid weight gain, venous thrombosis, and large ovarian cysts. Decreased CrCl, hemoconcentration, hypoproteinemia, elevated liver enzymes, elevated WBC, and electrolyte imbalances may also be present. Treatment is primarily symptomatic and includes fluid and electrolyte management, analgesics, and prevention of thromboembolic complications.

There is no sufficient scientific evidence traceable regarding use and safety of Clomiphene in concurrent use with alcohol.

Clomiphene is present in breast milk.

The adverse reactions related to Clomiphene can be categorized as

Common Adverse effects:

Ovarian hyperstimulation syndrome (OHSS), ovarian enlargement and cyst formation (high doses or prolonged treatment), visual disturbances (e.g. blurred vision, scintillating scotomata, phosphenes), multiple or ectopic pregnancy, new-onset or exacerbation of endometriosis

Less Common Adverse effects:

Hypertriglyceridaemia, hypersensitivity reactions (including anaphylaxis and angioedema)

Rare Adverse effects:

Nausea, vomiting, abdominal symptoms or pelvic discomfort (e.g. distention, bloating, pain), pancreatitis.

Symptoms: Nausea, vomiting, vasomotor flushes, blurred vision, scotomata, ovarian enlargement with pelvic or abdominal pain.

Management: Symptomatic and supportive treatment. Perform gastrointestinal decontamination.

Pharmacodynamics:

Clomiphene is a racemic mixture consisting of zuclomiphene (~38%) and enclomiphene (~62%), each with distinct pharmacologic properties. Clomiphene acts at the level of the hypothalamus, occupying cell surface and intracellular estrogen receptors (ERs) for longer durations than estrogen. This interferes with receptor recycling, effectively depleting hypothalamic ERs and inhibiting normal estrogenic negative feedback. Impairment of the feedback signal results in increased pulsatile GnRH secretion from the hypothalamus and subsequent pituitary gonadotropin (FSH, LH) release, causing growth of the ovarian follicle, followed by follicular rupture

Pharmacokinetics:

Absorption: Readily absorbed from the gastrointestinal tract. Time to peak plasma concentration: Approx 6 hours.

Metabolism: Metabolized in the liver; undergoes enterohepatic recirculation.

Excretion: Mainly via faeces (42%); urine (8%). Elimination half-life: Approx 5 days.

1. https://www.uptodate.com/contents/ Clomiphene -drug-information?search= Clomiphene &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/ Clomiphene _2015-1215.pdf
4. https://www.mims.com/india/drug/info/ Clomiphene ?type=full&mtype=generic#mechanism-of-action