Pregina Special Precautions

Ovarian Hyperstimulation Syndrome (OHSS): Clomifene citrate alone or in combination with gonadotropins has been reported to cause ovarian hyperstimulation syndrome (OHSS). Early warning signs of OHSS include 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. In severe cases, OHSS can induce gross ovarian enlargement, gastrointestinal symptoms, ascites, dyspnea, oliguria, and pleural effusion. OHSS has been associated with transient liver function test abnormalities suggestive of hepatic dysfunction may be accompanied by morphologic changes on liver biopsy.
Severe forms of OHSS have been reported rarely with the use of clomifene (either alone or in combinalion with gonadotropins). Pericardial effusion, anasarca, hydrothorax, acute abdomen, renal failure, pulmonary edema, hypotension, intraperitoneal and ovarian hemorrhage, deep venous thrombosis, torsion of the ovary, and acute respiratory distress occurred in these patients. Death due to hypovolemic shock, hemoconcentration or thromboembolism has occurred. If conception results, rapid progression to the severe form of the syndrome may occur.
The lowest dose consistent with expected clinical results should be used to minimize the hazard associated with occasional abdominal ovarian enlargement, associated with clomifene citrate therapy. Maximal enlargement of the ovary, whether physiologic or abnormal, may not occur until several days after discontinuation of the drug. Some patients with PCOS who are unusually sensitive to gonadotropins may experience an exaggerated response to usual doses of clomifene. Patients with PCOS should be started on the lowest recommended dose and shortest treatment duration for the first course of therapy.
Patients should be advised of tile possibility of ovarian cyst formation during therapy and should be instructed to return for repeat pelvic examination between 2 to 3 weeks after starting each course of treatment. Patients should inform their attending physician of any abdominal or pelvic pain, weight gain, discomfort or distention after taking clomifene.
Patients who complain of pain in the pelvic or abdominal area should be examined to rule out ovarian cyst formation or other cause. Due to fragility of enlarged ovaries in severe cases, abdominal and pelvic examination should be performed carefully.
Unless the ovaries have returned to its pretreatment size, additional dose of clomifene should not be given in patients. The dose or duration of the next course should be reduced. Clomifene-induced ovarian enlargement and cyst formation regress spontaneously within a few days or weeks after discontinuation of treatment. Cystic enlargement should always be managed conservatively unless surgical indication exists.
Visual Symptoms: Blurring and/or other visual symptoms such as spots or flashes (scintillating scotomata), diplopia, phosphenes, or photopobia may occur occasionally during therapy. These symptoms appear to be related to the dose and duration of treatment and generally disappear within a few days or weeks after discontinuation.
Patients should be warned that visual symptoms may make activities such as driving or operating machinery more hazardous than usual under conditions of variable lighting. These visual symptoms are usually reversible; however, cases of prolonged visual disturbances may be irreversible especially with increased dosage and duration of therapy. It is recommended to discontinue treatment and a complete ophthalmologic evaluation be performed if a patient has any visual symptoms.
Diagnosis Prior to Clomifene Therapy: The incidence of anovulatory disorders and the tendency to develop endometrial carcinoma increases with age. Prior to clomifene therapy in such patients, dilatation and curettage should always be done for diagnosis. Full diagnostic measures are mandatory if abnormal bleeding is present.
Ovarian Cancer: Fertility drugs have been rarely associated with ovarian cancer with infertility itself being a primary risk factor. Since epidemiological data suggest that prolonged therapy with clomifene citrate may increase this risk, the recommended duration of treatment should not be exceeded.
Uterine Fibroids: Patients with uterine fibroids should use clomifene with caution because of the risk of further enlargement of the fibroids.
Hepatic Impairment: Clomifene is not recommended in these patients (see Contraindications) and therefore clinical evaluation of liver function should always precede therapy.
Pre-existing Mental Depression or Thrombophlebitis: Use clomifene with caution in patients with pre-existing mental depression or thrombophlebitis to avoid the risk of exacerbation of the disease.
Effects on Ability to Drive and Use Machines: Patient should be warned that visual symptoms may make activities such as driving or operating machinery more hazardous than usual under conditions of variable lighting.
Use in Pregnancy: Teratogenic/Non-teratogenic Effects: In clinical studies, the overall incidence of birth anomalies resulting from clomifene ingestion during pregnancy was within range of that reported for the general population.
Pregnancy Wastage: A pregnancy (single and multiple) wastage or fetal loss rate of 21.4% (abortion rate of 19%), ectopic pregnancies 1.18%, hydatidiform mole 0.17%, fetal papyraceous 0.04%, and pregnancies with one or more still births 1.01% have been observed in patients of all diagnoses during clinical investigation of clomifene citrate.
Multiple Pregnancy: Treatment with clomifene citrate increases the chance of multiple pregnancy (including triplets, quadruplets and quintuplets). The incidence of multiple pregnancy was 7.9% in clinical studies. Among these pregnancies, 6.9% were twin, 0.5% triplet, 0.3% quadruplet, and 0.13% quintuplet. The ratio of monozygotic to dizygotic twins was 1:5 of the twin pregnancies. Before starting treatment, the patient and her spouse should be advised of the frequency and potential hazards of multiple pregnancy.
Combination therapy with clomifene citrate and chorionic gonadotropin has resulted in simultaneous bilateral tubal pregnancy, an extremely rare form of twin pregnancy.
Ectopic Pregnancy: An increased risk of ectopic pregnancy (including tubal and ovarian sites) has been observed in women who conceive after clomifene therapy.
Use in Children: Clomifene citrate is not intended for use in children.
Use in the Elderly: Clomifene is not intended for use in the elderly.