Ovulant

Clomifene is a selective estrogen receptor modulator (SERM) that increases production of gonadotropins by inhibiting negative feedback on the hypothalamus. It is used mainly in female infertility, mainly as ovarian stimulator, such as part of an in vitro fertilization procedure.
Characterized by white to off-white uncoated tablet, round, flat, plain on one side and bisected on the other side.
Each tablet contains: Clomifene Citrate, USP 50 mg.

Pharmacology: Pharmacodynamics: Clomifene citrate is a drug of considerable pharmacologic potency. With careful selection and proper management of the patient, Clomifene citrate has been demonstrated to be a useful therapy for the anovulatory patient desiring pregnancy.
Clomifene 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. Clomifene 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 clomifene 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.
Clomifene citrate has no apparent progestational, androgenic, or antiandrogenic effects and does not appear to interfere with pituitary-adrenal or pituitary-thyroid function. Although there is no evidence of a "carryover effect" of Clomifene citrate, spontaneous ovulatory menses have been noted in some patients after Clomifene citrate therapy.
Mechanism of Action: Clomifene appears to inhibit estrogen in hypothalamus, thereby inhibiting negative feedback of estrogen on gonadotropin production. It may also result in direct stimulation of the hypothalamic-pituitary axis. Zuclomifene, a more active isomer, stays bound for long period of time.
In normal physiologic female hormonal cycling, at 7 days past ovulation, high levels of estrogen and progesterone produced from the corpus luteum inhibit GnRH, FSH and LH at the hypothalamus and anterior pituitary. If fertilization does not occur in the post-ovulation period, the corpus luteum disintegrates due to lack of beta-HCG. This would normally be produced by the embryo in the effort of maintaining progesterone and estrogen levels during pregnancy.
Therapeutically, clomifene is given early in the menstrual cycle. It is typically prescribed beginning on day 1, 3 or 5 and continuing for 5 days. By the time, FSH level is rising steadily, causing development of a few follicles. Follicles in turn produce the estrogen, which circulated in serum. In the presence of clomifene, the body perceives a low level of estrogen, similar to a day 22 in the previous cycle. Since estrogen can no longer effectively exert negative feedback on the hypothalamus, GnRH secretion becomes more rapidly pulsatile, which results in increased pituitary gonadotropin (FSH, LH) release. (It should be noted that more rapid, lower amplitude pulses of GnRH lead to increased LH/FSH secretion, while more irregular, larger amplitude pulses of GnRH leads to a decrease in the production of LH/FSH). Increased FSH level causes growth of more ovarian follicles, and subsequently rupture of follicles resulting in ovulation.
Pharmacokinetics: Clomifene citrate is absorbed from the gastrointestinal tract. It is metabolized in the liver and slowly excreted via the bile. Unchanged drug and metabolites are excreted in the feces. The biological half-life is reported to be 5 days although traces are found in the feces for up to 6 weeks. Enterohepatic recirculation takes place.

For the treatment of anovulatory infertility.

First course: 50 mg daily for 5 days. If ovulation appears not to have occurred, a second course of 100 mg daily for 5 days should be given. Maximum dose is 100 mg/day for 5 days.

Signs and Symptoms: Toxic effects accompanying acute overdosage of Clomifene citrate have not been reported. Signs and symptoms of overdosage as a result of the use of more than the recommended dose during Clomifene citrate therapy include nausea, vomiting, vasomotor flushes, visual blurring, spots or flashes, scotomata, ovarian enlargement with pelvic or abdominal pain.
Treatment: In the event of overdose, appropriate supportive measures should be employed in addition to gastrointestinal decontamination.

Liver disease; history of liver dysfunction; abnormal bleeding of undetermined origin; pregnancy.

Visual Symptoms: Patients should be advised that blurring or other visual symptoms such as spots or flashes (scintillating scotomata) may occasionally occur during therapy with Clomifene citrate. These visual symptoms increase in incidence with increasing total dose or therapy duration. These visual disturbances are usually reversible; however, cases of prolonged visual disturbance have been reported with some occurring after Clomifene citrate discontinuation. The visual disturbances may be irreversible, especially with increased dosage or duration of therapy. 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.
The visual symptoms appear to be due to intensification and prolongation of afterimages. Symptoms often first appear or are accentuated with exposure to a brightly lit environment. While measured visual acuity usually has not been affected, a study patient taking 200 mg Clomifene citrate daily developed visual blurring on the 7th day of treatment, which progressed to severe diminution of visual acuity by the 10th day. No other abnormality was found, and the visual acuity returned to normal on the 3rd day after treatment was stopped.
Ophthalmologically definable scotomata and retinal cell function (electroretinographic) changes have also been reported. A patient treated during clinical studies developed phosphenes and scotomata during prolonged Clomifene citrate administration, which disappeared by the 32nd day after stopping therapy.
While the etiology of these visual symptoms is not yet understood, patients with any visual symptoms should discontinue treatment and have a complete ophthalmological evaluation carried out promptly.
Ovarian Hyperstimulation Syndrome: The ovarian hyperstimulation syndrome (OHSS) has been reported to occur in patients receiving Clomifene citrate therapy for ovulation induction. OHSS may progress rapidly (within 24 hours to several days) and become a serious medical disorder. In some cases, OHSS occurred following cyclic use of Clomifene citrate therapy or when Clomifene citrate was used in combination with gonadotropins. Transient liver function test abnormalities suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver biopsy, have been reported in association with OHSS.
OHSS is a medical event distinct from uncomplicated ovarian enlargement. The clinical signs of this syndrome in severe cases can include gross ovarian enlargement, gastrointestinal symptoms, ascites, dyspnea, oliguria, and pleural effusion. In addition, the following symptoms have been reported in association with this syndrome: pericardial effusion, anasarca, hydrothorax, acute abdomen, hypotension, renal failure, pulmonary edema, intraperitoneal and ovarian hemorrhage, deep venous thrombosis, torsion of the ovary, and acute respiratory distress. The early warning signs of OHSS are abdominal pain and distention, nausea, vomiting, diarrhea, and weight gain. Elevated urinary steroid levels, varying degrees of electrolyte imbalance, hypovolemia, hemoconcentration, and hypoproteinemia may occur. Death due to hypovolemic shock, hemoconcentration, or thromboembolism has occurred. Due to fragility of enlarged ovaries in severe cases, abdominal and pelvic examination should be performed very cautiously. If conception results, rapid progression to the severe form of the syndrome may occur.
To minimize the hazard associated with occasional abnormal ovarian enlargement associated with Clomifene citrate therapy, the lowest dose consistent with expected clinical results should be used. Maximal enlargement of the ovary, whether physiologic or abnormal, may not occur until several days after discontinuation of the recommended dose of Clomifene citrate. Some patients with polycystic ovary syndrome who are unusually sensitive to gonadotropin may have an exaggerated response to usual doses of Clomifene citrate. Therefore, patients with polycystic ovary syndrome should be started on the lowest recommended dose and shortest treatment duration for the first course of therapy.
If enlargement of the ovary occurs, additional Clomifene citrate 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. Ovarian enlargement and cyst formation associated with Clomifene citrate therapy usually regresses spontaneously within a few days or weeks after discontinuing treatment. The potential benefit of subsequent Clomifene citrate therapy in these cases should exceed the risk. Unless surgical indication for laparotomy exists, such cystic enlargement should always be managed conservatively.
A causal relationship between ovarian hyperstimulation and ovarian cancer has not been determined. However, because a correlation between ovarian cancer and nulliparity, infertility, and age has been suggested, if ovarian cyst do not regress spontaneously, a thorough evaluation should be performed to rule out the presence of ovarian neoplasia.

Clomifene should not be used during pregnancy or by women who have liver disease, ovarian cysts, hormone-dependent tumors, or undiagnosed vaginal bleeding.

Fetal Risk Summary: Pregnancy Category X. Clomifene citrate use in pregnant women is contraindicated, as Clomifene citrate treatment does not offer benefit in this population.
Available human data do not suggest an increased risk for congenital anomalies above the background population risk. However, animal reproductive toxicology studies showed increased embryo-fetal and structural malformations in offspring. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risks to the fetus.
Clinical Considerations: To avoid inadvertent Clomifene citrate administration during early pregnancy, appropriate tests should be utilized during each treatment cycle to determine whether ovulation and/or pregnancy occurs. Patients should be evaluated carefully to exclude ovarian enlargement or ovarian cyst formation between each treatment cycle. The next course of Clomifene citrate therapy should be delayed until these conditions have been excluded.
Lactation: It is not known whether Clomifene citrate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if Clomifene citrate is administered to a nursing woman. In some patients, Clomifene citrate may reduce lactation.

Abdominal pain, diarrhea, dyspepsia, flatulence, nausea, dizziness, headache, pharyngitis, rhinitis, sinusitis, upper respiratory tract infections, back pain, insomnia, rash.

Ace inhibitor, furosemide, aspirin, fluconazole, lithium, warfarin, antacids, glucocorticoids, thiazides or loop diuretics.

Store at temperatures not exceeding 30°C.

Trophic Hormones & Related Synthetic Drugs

G03GB02 - clomifene ; Belongs to the class of synthetic agents used as ovulation stimulants.

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