The purpose and risks of Clomid therapy should be presented to the patient before starting treatment. It should be emphasized that the goal of Clomid therapy is ovulation for subsequent pregnancy. The physician should counsel the patient with special regard to the following potential risks:
Ovarian Hyperstimulation Syndrome: Ovarian Hyperstimulation Syndrome (OHSS) has been reported in patients receiving Clomid therapy for ovulation induction. In some cases, OHSS occurred following the cyclic use of Clomid therapy or when Clomid was used in combination with gonadotropins. Rare cases of severe forms of OHSS have been reported where the following symptoms have occurred: 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 Clomid 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 Clomid. Maximal enlargement of the ovary may not occur until several days after discontinuation of the course of Clomid. Some patients with polycystic ovary syndrome who are unusually sensitive to gonadotropin may have an exaggerated response to usual doses of Clomid.
The patient who complains of abdominal or pelvic pain, discomfort, or distension after taking Clomid 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 Clomid should not be given until the ovaries have returned to pre-treatment size. Ovarian enlargement and cyst formation associated with Clomid 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 Clomid. The patient should be instructed to inform the physician whenever any unusual visual symptoms occur. These visual disturbances are usually reversible ; however, cases of prolonged visual disturbance have been reported including after Clomid discontinuation. The visual disturances may be irreversible, especially with increased dosage or duration of therapy (See sections 4.7 and 4.8). 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. 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.
Cases of hypertriglyceridemia have been reported (see section 4.8 Undesirable effects) in the post-marketing experience with Clomid 50mg Tablets. Pre-existing or family history of hyperlipidemia and use of higher than recommended dose and/or longer duration of treatment with Clomid 50mg Tablets are associated with risk of hypertriglyceridemia.
Periodic monitoring of plasma triglycerides may be indicated in these patients.
Treatment with Clomid should only be undertaken by a specialist having available the appropriate facilities for close supervision of clinical and laboratory responses. The patient's physical state and the aetiological diagnosis should be carefully investigated prior to this therapy. Any pre-existent endocrine defect or other cause of infertility in patients or partner should be examined and treated prior to this therapy.
Multiple Pregnancy: There is an increased chance of multiple pregnancy when conception occurs in relationship to Clomid therapy. During the clinical investigation studies, the incidence of multiple pregnancy was 7.9% (186 of 2369 Clomid 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 Clomid therapy. Ectopic pregnancy associated with Clomid involves a multiple pregnancy with coexisting extrauterine and intrauterine gestations.
Uterine Fibroids: Caution should be exercised when using Clomid in patients with uterine fibroids due to potential for further enlargement of the fibroids.
Pregnancy loss and Birth Anomalies: The overall incidence of reported birth anomalies from pregnancies associated with maternal Clomid 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 Clomid, 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 Clomid or occurred naturally.
The patient should be informed of the greater pregnancy risks associated with certain characteristics or conditions of any pregnant woman: eg. 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 Clomid is being considered. Based upon the evaluation of the patient, genetic counselling may be indicated.
Population based reports have been published on possible elevation of risk of Down's Syndrome in ovulation induction cases and of increase in trisomy defects among spontaneously aborted foetuses from subfertile women receiving ovulation inducing drugs (no women with Clomid alone and without additional inducing drug). However, as yet, the reported observations are too few to confirm or not confirm the presence of an increased risk that would justify amniocentesis other than for the usual indications because of age and family history.
The experience from patients of all diagnosis during clinical investigation of Clomid shows a pregnancy (single and multiple) loss or foetal loss rate of 21.4% (abortion rate of 19.0%), ectopic pregnancies, 1.18%, hydatidiform mole, 0.17%, foetus papyraceous, 0.04% and of pregnancies with one or more stillbirths, 1.01%.
Clomid 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 Clomid 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. Epidemiological data suggest that prolonged use of Clomid may increase this risk. Therefore the recommended duration of treatment should not be exceeded (see dosage and administration).
Patients with rare hereditary problems of fructose/galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.