Renata Limited


Full Prescribing Info
Clomifene citrate.
Pharmacology: Pharmacodynamics: Clomifene is a non-steroidal compound with weak estrogenic and moderate antiestrogenic properties. Clomifene induces ovulation by increasing the output of pituitary gonadotropins. It binds competitively to estrogen receptors, decreasing the sites available to endogenous estrogen. The decreased binding of endogenous estrogen to hypothalamic and pituitary estrogen receptors results in increased secretion of luteinizing hormone-releasing hormone (LH-RH) and follicle-stimulating hormone-releasing hormone (FSH-RH) followed by the gonadotropins LH and FSH. In females, the gonadotropins stimulate maturation and endocrine activity of the ovarian follicle which is followed by the development and function of the corpus luteum.
In a hypothetical Clomifene induced ovulatory cycle resulting in successful ovulation, the initial endocrine event is an increase in LH and FSH levels. LH and FSH levels decline following discontinuation of Clomifene, but then surge at mid-cycle. Concomitantly, a sustained increase in estradiol is seen beginning with Clomifene administration and ending at a preovulatory peak. With successful ovulation, a substantial increase in progesterone levels is seen, indicating the formation of a functional corpus luteum.
Ovulation occurs 6 to 12 days after a course of therapy.
Pharmacokinetics: Absorption: Clomifene citrate is readily absorbed from the gastrointestinal tract.
Metabolism: It is metabolised in the liver and slowly excreted via the bile. Enterohepatic circulation occurs.
Elimination: The majority of unchanged drug and its metabolites are excreted in the feces. The biological half-life is reported to be 5 days although traces are found in the faeces for up to 6 weeks. Appearance of the drug after 6 weeks suggests enterohepatic recirculation of the drug and metabolites. A small amount of unchanged drug and its metabolites is excreted in the urine and detectable for 6 weeks.
Clomifene citrate is indicated for the treatment of ovulatory failure.
Clomifene citrate is indicated only for patients in whom ovulatory dysfunction is demonstrated, who meet the conditions described in this prescribing information and for whom Clomifene is not contraindicated.
Other causes of infertility must be excluded or adequately treated before giving Clomifene citrate. Good levels of endogenous estrogen (as estimated from vaginal smears, endometrial biopsy, assay of urinary estrogen or endometrial bleeding in response to progesterone) provide a favorable prognosis for ovulatory response induced by Clomifene citrate. A low level of estrogen although clinically less favorable does not preclude successful outcome of therapy.
Clomifene Citrate therapy is ineffective in patients with primary pituitary or primary ovarian failure. Clomifene citrate therapy cannot be expected to substitute for specific treatment of other causes of ovulatory failure, such as thyroid or adrenal disorders.
Dosage/Direction for Use
General Considerations: The work-up and treatment of candidates for Clomifene citrate therapy should be supervised by physicians experienced in management of gynecologic or endocrine disorders. Patients should be chosen for therapy with Clomifene citrate only after careful diagnostic evaluation. The plan of therapy should be outlined in advance. Impediments to achieving the goal of therapy must be excluded or adequately treated before giving Clomifene citrate.
Many patients will respond to 50 mg daily for 5 days. In the determination of a recommended starting dose schedule, efficacy must be balanced against potential adverse effects. For example, the data available so far suggest that ovulation and pregnancy are slightly more attainable on 100 mg/day for 5 days than on 50 mg/day for 5 days.
As the dosage is increased, however, ovarian hyperstimulation and other adverse affects may be expected to increase. Furthermore, although the data do not yet establish a relationship between dosage and multiple births, it would seem reasonable on pharmacologic grounds that such a relationship does exist.
For these reasons, it would seem prudent to begin the treatment of the usual patient with a lower dose, 50 mg daily for 5 days, and to increase the dose only in those patients who do not respond to the first course. Special care with lower 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.
Recommended Dosage: The recommended dose for the first course of Clomifene citrate is 50 mg daily for 5 days.
Therapy may be started at any time in the patient who has had no recent uterine bleeding. If progestin-induced bleeding is planned, or if spontaneous uterine bleeding occurs before therapy, the regimen of 50 mg daily for 5 days should be started on or about the fifth day of the cycle. When ovulation occurs at this dosage, there is no advantage to increasing the dose in subsequent cycles of treatment.
If ovulation appears not to have occurred after the first course of therapy, a second course of 100 mg daily (two 50 mg tablets given as a single daily dose) for 5 days should be given. This course may be started as early as 30 days after the previous one.
Increase of the dosage or duration of therapy beyond 100 mg/day for 5 days should not be undertaken.
The majority of patients who are going to respond will respond to the first course of therapy, and 3 courses should constitute an adequate therapeutic trial. If ovulatory menses have not yet occurred, the diagnosis should be re-evaluated. Treatment beyond this is not recommended in the patient who does not exhibit evidence of ovulation.
Pregnancy: The importance of properly timed coitus cannot be overemphasized. For regularity of cyclic ovulatory response it is also important that each course of Clomifene citrate be started on or about the fifth cycle day, once ovulation has been established.
As with other therapeutic modalities, Clomifene citrate therapy follows the rule of diminishing returns, such that likelihood of conception diminishes with each succeeding course of therapy. Before starting treatment, patients should be advised of the possibility of multiple pregnancy and its potential hazards if conception occurs in relationship to Clomifene citrate therapy.
Long-term cyclic therapy not recommended: Since the relative safety of long term cyclic therapy has not yet been conclusively demonstrated and since the majority of patients will ovulate following 3 courses long-term cyclic therapy is not recommended, i.e. beyond a total of about 6 cycles (including 3 ovulatory cycles).
Route of Administration: Oral.
Symptoms: Mild to moderate toxicity: Includes flushing abdominal pain, ovarian enlargement, pelvic pain, nausea, vomiting, visual blurring, spots or flashes, and scotomata. Mild ovarian hyperstimulation symptoms include nausea, vomiting, diarrhea, and weight gain.
Severe toxicity: Severe ovarian hyperstimulation syndrome may include gross ovarian enlargement, ascites, dyspnea, oliguria, pleural effusion, pericardial effusion, anasarca, acute abdominal pain, hypotension, renal failure, pulmonary edema, intraperitoneal and ovarian hemorrhage, ovarian torsion, deep venous thrombosis, respiratory distress, electrolyte imbalances, hypovolemia, hypoproteinemia, hemoconcentration, and shock.
Maximal enlargement of the ovary may not occur until several days after discontinuation of the course of Clomifene citrate. Female patients of reproductive age who have taken an overdose should be observed for 2 or 3 weeks for ovarian enlargement.
Treatment: Most exposures are mild and require only supportive care. In severe toxicity, support respiratory and cardiovascular function as needed. For patients with severe ovarian hyperstimulation syndrome, initiate intravenous hydration, monitor fluid input and output, and initiate deep venous thrombosis prophylaxis.
Uncontrolled thyroid or adrenal dysfunction.
Liver disease or a history of liver dysfunction.
Abnormal uterine bleeding.
Endometrial carcinoma.
Hormone dependent tumors.
Ovarian cysts.
Organic intracranial lesion.
Hypersensitivity to Clomifene.
Special Precautions
Clomifene should not be used in patients with pre-existing mental depression or thrombophlebitis because of the risk of exacerbation.
Ovarian hyperstimulation syndrome and abnormal ovarian enlargement may occur, lowest dose is suggested to minimize this complication.
Ovarian cyst: Pelvic examination is necessary prior to start of and before each subsequent course of Clomifene citrate treatment. Clomifene citrate should not be given in the presence of an ovarian cyst (including endometriosis involving the ovary) except polycystic ovary since further enlargement of the cyst may occur. The lowest doses possible should be used to minimise ovarian enlargement or cyst formation; some patients with polycystic ovary syndrome may have an exaggerated response to usual doses of Clomifene. Patients should be instructed to report any abdominal or pelvic pain, distension, or weight gain, as this may indicate the presence or enlargement of ovarian cysts. They should also be evaluated for the presence of ovarian cysts before each cycle of treatment. If abnormal enlargement occurs, Clomifene should not be given until the ovaries have returned to pre-treatment size, and subsequent doses should be reduced.
Clomifene should be used with caution in patients with uterine fibroids, due to the potential for enlargement of the fibroids.
Multiple pregnancies: There is an increased chance of multiple pregnancies when conception occurs in relationship to Clomifene citrate therapy. The potential complications and hazards of multiple pregnancies should be discussed with the patient.
Pregnancy wastage and birth anomalies: The patient should be informed of the greater pregnancy risks associated with certain characteristics or conditions of any pregnant woman: e.g., age of female and male partner, history of spontaneous abortions, Rh genotype, abnormal menstrual history, infertility history (regardless of cause), organic heart disease, diabetes, exposure to infectious agents such as rubella, familial history of birth anomaly, and other risk factors that may be pertinent to the patient for whom Clomifene citrate is being considered. Based upon the evaluation of the patient, genetic counselling may be indicated.
Visual symptoms: Patients should be advised that blurring or other visual symptoms may occasionally occur during or shortly after therapy with Clomifene citrate. The significance of these visual symptoms is not understood. If the patient has any visual symptoms, treatment should be discontinued and complete ophthalmologic evaluation performed.
Long-term cyclic therapy is not recommended, because of the uncertainty regarding increased risk of ovarian cancer: a maximum of 6 cycles of treatment has generally been advised.
Effects on the ability to drive and use machines: Patients should be warned that visual symptoms may render such activities as driving a car or operating machinery more hazardous than usual, particularly under conditions of variable lighting.
Use In Pregnancy & Lactation
Pregnancy: Clomifene use is contraindicated during pregnancy. Prior to administration of each cycle of Clomifene treatment, pregnancy should be ruled out.
Lactation: Lactation studies with Clomifene have not been conducted in humans, and it is not known whether it is excreted into human milk. Clomifene may reduce lactation in some nursing women. Caution should be exercised when administering Clomifene to a nursing woman.
Adverse Reactions
The incidence and severity of adverse effects of Clomifene citrate tend to be related to the dose used.
Common: Cardiovascular: Syncope.
Dermatologic: Acne, Dermatitis, Dry hair, Erythema, Erythema multiforme, Erythema nodosum, Vasomotor Flushes, Hypertrichosis, Loss of hair, Pruritus, Rash, Urticaria.
Endocrine metabolic: Disorder of thyroid gland, Weight decreased , Weight increased.
Gastrointestinal: Abdominal-pelvic discomfort (distention, bloating), acute abdominal pain, Constipation, Diarrhea, Gastrointestinal tract finding, Increased appetite), nausea and vomiting.
Hepatic: Increased liver enzymes.
Musculoskeletal: Arthralgia, Backache, Myalgia.
Neurologic: Asthenia, Dizziness, Headache, Insomnia, Light-headedness, Migraine, Paresthesia, Unsteady when walking, Vertigo.
Ophthalmic: Eye/vision finding, temporary functional visual loss, Pain in eye, Photopsia.
Otic: Tinnitus.
Psychiatric: Anxiety, Depression, Fatigue, Feeling nervous, Irritability, Mood disorder.
Renal: Polyuria.
Reproductive: Cyst of ovary, Endometriosis, Hyperstimulation of ovaries, Pain of breast.
Urogenital finding: Vaginal dryness.
Other: Fever.
Serious: Cardiovascular: Cardiac dysrhythmia, Chest pain, Edema, Hypertension, Palpitations, Phlebitis, Pulmonary embolism, Tachycardia.
Endocrine metabolic: Gynecomastia.
Gastrointestinal: Pancreatitis, acute.
Hematologic: Leukocytosis, Thrombophlebitis.
Hepatic: Hepatitis, Liver carcinoma.
Neurologic: Cerebrovascular accident, Neoplasm of nervous system, Seizure.
Ophthalmic: Cataract, Macular retinal edema, Optic neuritis, Posterior vitreous detachment, Retinal hemorrhage, Retinal vascular disorder, Thrombosis of retinal artery, Thrombosis of retinal vein.
Psychiatric: Psychotic disorder.
Reproductive: Disorder of menstruation, Ectopic pregnancy, Endometrial carcinoma, Gestational trophoblastic neoplasm, Hemorrhagic cyst of ovary, Hypertrophy of ovary, Neoplasm of ovary, Ovarian cancer, Testicular cancer, Tubal pregnancy, Uterine hemorrhage.
Other: Carcinoma of breast, Fetal neoplasm, Gestational trophoblastic neoplasm, Malignant neoplasm of liver, Neoplasm of breast, Neoplasm of endometrium, Neoplasm of nervous system, Neoplasm of ovary.
Ovarian Enlargement: At recommended dosage, abnormal ovarian enlargement is infrequent, although the usual cyclic variation in ovarian size may be exaggerated. Similarly, cyclic pain (mittelschmerz) may be accentuated. With higher or prolonged dosage, more frequent ovarian enlargement and cyst formation may occur, and the luteal phase of the cycle may be prolonged.
Drug Interactions
None known/No information available.
Store below 30°C. Protect from heat, light, excessive humidity and store in pack.
Shelf-Life: 24 months.
ATC Classification
G03GB02 - clomifene ; Belongs to the class of synthetic agents used as ovulation stimulants.
Tab 50 mg (white, round flat bevel edge, both side of the tablet is plain) x 1 x 10's.
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