Clomiphene Citrate Tablets USP

Clomiphene Citrate Tablets USP 50 mg- is indicated for the treatment of ovulatory failure in women desiring pregnancy. Clomiphene citrate tablet is indicated only for patients in whom ovulatory dysfunction is demonstrated. Other causes of infertility must be excluded or adequately treated before giving Clomiphene citrate tablet.

Adults
The recommended dose for the first course of Clomiphene citrate tablet is 50 mg (1 tablet) 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 reevaluated.
Treatment beyond this is not recommended in the patient who does not exhibit evidence of ovulation.
Long-term cyclic therapy:
Not recommended.
Efficacy and safety of clomiphene for more than 6 treatment cycles have not been demonstrated.
Special Populations
Special care with lower dosage or duration of treatment is particularly recommended if unusual sensitivity to pituitary gonadotrophin is suspected, such as in patients with polycystic ovary syndrome.

Symptoms/Signs/Conditions: Adverse effects appeared to be dose-related, occurring more frequently at the higher dose and with the longer courses of treatment used in investigational studies. At recommended dosage, adverse effects are not prominent and infrequently interfere with treatment.
During the investigational studies, the more commonly reported adverse effects included ovarian enlargement (13.6%), vasomotor flushes (10.4%), abdominal–pelvic discomfort (distention, bloating) (5.5%), nausea and vomiting (2.2%), breast discomfort (2.1%), visual symptoms (1.5%), headache (1.3%) and intermenstrual spotting or menorrhagia (1.3%).
Ovarian enlargement: At recommended dosage, abnormal ovarian enlargement is infrequent although the usual cyclic variation in ovarian size may be exaggerated. Similarly, cyclic ovarian 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.
Rare instances of massive ovarian enlargement are recorded. Such an instance has been described in a patient with polycystic ovary syndrome whose Clomiphene citrate tablet therapy consisted of 100 mg daily for 14 days. Abnormal ovarian enlargement usually regresses spontaneously; most of the patients with this condition should be treated conservatively.
Immune system disorders: Not known: Hypersensitivity reactions including anaphylaxis and angioedema.
Eye/Visual Symptoms: Symptoms described usually as “blurring” or spots or flashes (scintillating scotomata) increase in incidence with increasing total dose. These symptoms appear to be due to intensification and prolongation of after-images. After-images as such have also been reported. Symptoms often first appear or are accentuated with exposure to bright-light environment. Ophthalmologically definable scotomata, phosphenes and reduced visual acuity have been reported. There are rare reports of cataracts and optic neuritis. These visual disturbances are usually reversible. However, cases of prolonged visual disturbance have been reported, including after Clomiphene citrate tablet have been discontinued. The visual disturbances may be irreversible, especially with increased dosage or duration of therapy.
Genitourinary: There are reports of new cases of endometriosis and exacerbation of pre-existing endometriosis during Clomiphene citrate tablet therapy. Multiple pregnancies, including simultaneous intrauterine and extrauterine pregnancies, have been reported. There is an increased chance of ectopic pregnancy in women who conceive following Clomiphene citrate tablet therapy. Reduced endometrial thickness (frequency not known).
Tumours/neoplasms: Isolated reports have been received on the occurrence of endocrine-related or dependent neoplasms or their aggravation.
Central nervous system: Convulsions have been reported; patients with a history of seizures may be predisposed, transient paraesthesia (frequency not known), dizziness (frequency not known). In investigational patients, CNS symptoms/signs, conditions of dizziness, light-headedness/vertigo (0.9%), nervous tension/insomnia (0.8%) and fatigue/depression (0.7%) were reported. After prescription availability, there were isolated additional reports of these conditions and also reports of other conditions such as syncope/fainting, cerebrovascular accident, cerebral thrombosis, psychotic reactions including paranoid psychosis, neurologic impairment, disorientation and speech disturbance.
Psychiatric disorders: Anxiety (frequency not known), depression (frequency not known), mood disturbances (including mood altered, mood swings and irritability) (frequency not known), nervousness (frequency not known), insomnia (frequency not known).
Skin and subcutaneous tissue disorders: Dermatitis and rash were reported by investigational patients. Conditions such as rash and urticaria were the most common ones reported after prescription availability but also reported were conditions such as allergic reaction, ecchymosis and angioneurotic oedema. Hair thinning (alopecia) has been reported very rarely.
Liver function: Bromsulphalein (BSP) retention of greater than 5% was reported in 32 of 141 patients in whom it was measured, including 5 of 43 patients who took approximately the dose of Clomiphene citrate tablet now recommended. Retention was usually minimal unless associated with prolonged continuous Clomiphene citrate tablet administration or with apparently unrelated liver disease. Other liver function tests were usually normal. In a later study in which patients were given 6 consecutive monthly courses of Clomiphene citrate tablet (50 mg or 100 mg daily for 3 days) or matching placebo, BSP tests were done on 94 patients. Values in excess of 5% retention were recorded in 11 patients, 6 of whom had taken drug and 5 placebos. In a separate report, one patient taking 50 mg of Clomiphene citrate tablet daily developed jaundice on the 19th day of treatment; liver biopsy revealed bile stasis without evidence of hepatitis.
Metabolism disorders: Hypertriglyceridemia (frequency not known), in some cases with pancreatitis, has been observed in patients with preexisting or a family history of hypertriglyceridemia and/or with dose and duration of treatment exceeding the label recommendations.
Cardiac disorders: Tachycardia, (frequency not known) palpitations (frequency not known).
Hepatobiliary disorders: Increased Transaminases.
Gastrointestinal disorders: Pancreatitis (frequency not known).

General: Good levels of endogenous oestrogen (as estimated from vaginal smears, endometrial biopsy, assay of urinary oestrogen, or endometrial bleeding in response to progesterone) provide a favourable prognosis for ovulatory response induced by Clomiphene citrate tablet. A low level of oestrogen, although clinically less favourable, does not preclude successful outcome of therapy. Clomiphene citrate tablet therapy is ineffective in patients with primary pituitary or primary ovarian failure. Clomiphene citrate tablet therapy cannot be expected to substitute for specific treatment of other causes of ovulatory failure, such as thyroid or adrenal disorders. For hyperprolactinaemia there is other preferred specific treatment. Clomiphene citrate tablet is not first line treatment for low weight related amenorrhoea, with infertility, and has no value if a high FSH blood level is observed following an early menopause.
Ovarian Hyperstimulation Syndrome: Ovarian Hyperstimulation Syndrome (OHSS) has been reported in patients receiving Clomiphene citrate tablet therapy for ovulation induction. In some cases, OHSS occurred following the cyclic use of Clomiphene citrate tablet therapy or when Clomiphene citrate tablet was used in combination with gonadotropins. The following symptoms have been reported in association with this syndrome during Clomiphene citrate tablet therapy: pericardial effusion, anasarca, hydrothorax, acute abdomen, renal failure, pulmonary oedema, ovarian haemorrhage, deep venous thrombosis, torsion of the ovary and acute respiratory distress. If conception results, rapid progression to the severe form of the syndrome may occur.
To minimise the hazard of the abnormal ovarian enlargement associated with Clomiphene citrate tablet therapy, the lowest dose consistent with expectation of good results should be used. The patient should be instructed to inform the physician of any abdominal or pelvic pain, weight gain, discomfort or distension after taking Clomiphene citrate tablet. Maximal enlargement of the ovary may not occur until several days after discontinuation of the course of Clomiphene citrate tablet. Some patients with polycystic ovary syndrome who are unusually sensitive to gonadotropin may have an exaggerated response to usual doses of Clomiphene citrate tablet.
The patient who complains of abdominal or pelvic pain, discomfort, or distension after taking Clomiphene citrate tablet should be examined because of the possible presence of an ovarian cyst or other cause. Due to fragility of enlarged ovaries in severe cases, abdominal and pelvic examination should be performed very cautiously. If abnormal enlargement occurs Clomiphene citrate tablet should not be given until the ovaries have returned to pre-treatment size. Ovarian enlargement and cyst formation associated with Clomiphene citrate tablet therapy usually regress spontaneously within a few days or weeks after discontinuing treatment. Most of these patients should be managed conservatively. The dosage and/or duration of the next course of treatment should be reduced.
Visual Symptoms: Patients should be advised that blurring or other visual symptoms such as spots or flashes (scintillating scotomata) may occasionally occur during or shortly after therapy with Clomiphene citrate tablet. These visual disturbances are usually reversible; however, cases of prolonged visual disturbance have been reported including after Clomiphene citrate tablet discontinuation. The visual disturbances may be irreversible especially with increased dosage or duration of therapy. The significance of these visual symptoms is not understood. If the patient has any visual symptoms, treatment should be discontinued, and ophthalmologic evaluation performed.
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.
Hypersensitivity reactions: Hypersensitivity reactions including anaphylaxis and angioedema have been reported with Clomiphene citrate tablet use. In case of allergic reactions, treatment with Clomiphene citrate tablet must be discontinued and appropriate symptomatic treatment initiated.
Multiple Pregnancy: There is an increased chance of multiple pregnancy when conception occurs in relationship to Clomiphene citrate tablet therapy. The potential complications and hazards of multiple pregnancy should be discussed with the patient. During the clinical investigation studies, the incidence of multiple pregnancy was 7.9% (186 of 2369 Clomiphene citrate tablet associated pregnancies on which outcome was reported). Among these 2369 pregnancies, 165 (6.9%) twin, 11 (0.5%) triplet, 7 (0.3%) quadruplet and 3 (0.13%) quintuplet. Of the 165 twin pregnancies for which sufficient information was available, the ratio of monozygotic twins was 1:5.
Ectopic Pregnancy: There is an increased chance of ectopic pregnancy (including tubal and ovarian sites) in women who conceive following Clomiphene citrate tablet therapy. Multiple pregnancies, including simultaneous intrauterine and extrauterine pregnancies, have been reported.
Uterine Fibroids:
Caution should be exercised when using Clomiphene citrate tablet in patients with uterine fibroids due to potential for further enlargement of the fibroids.
Pregnancy Wastage and Birth Anomalies: The overall incidence of reported birth anomalies from pregnancies associated with maternal Clomiphene citrate tablet ingestion (before or after conception) during the investigational studies was within the range of that reported in the published references for the general population. Among the birth anomalies spontaneously reported in the published literature as individual cases, the proportion of neural tube defects has been high among pregnancies associated with ovulation induced by Clomiphene citrate tablet, but this has not been supported by data from population-based studies.
The physician should explain so that the patient understands the assumed risk of any pregnancy whether the ovulation was induced with the aid of Clomiphene citrate tablet or occurred naturally.
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 Clomiphene citrate tablet is being considered. Based upon the evaluation of the patient, genetic counselling may be indicated.
The experience from patients of all diagnosis during clinical investigation of Clomiphene citrate tablet shows a pregnancy (single and multiple) wastage or fetal loss rate of 21.4% (abortion rate of 19.0%), ectopic pregnancies, 1.18%, hydatidiform mole, 0.17%, fetus papyraceous, 0.04% and of pregnancies with one or more stillbirths, 1.01%. Clomiphene citrate tablet therapy after conception was reported for 158 of the 2369 delivered and reported pregnancies in the clinical investigations. Of these 158 pregnancies 8 infants (born of 7 pregnancies) were reported to have birth defects.
There was no difference in reported incidence of birth defects whether Clomiphene citrate tablet was given before the 19th day after conception or between the 20th and 35th day after conception. This incidence is within the anticipated range of general population.
Ovarian Cancer: There have been rare reports of ovarian cancer with fertility drugs; infertility itself is a primary risk factor.

Store in a dry place below 30°C and protect from light.
Keep out of reach of children.

1 x 10 Alu/PVC blister packs.
Hisrich-50 tablets are available in an Alu/PVC blister of 10 tablets. Such 01 blister in a unit carton with package insert.