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 clomiPHENE citrate. These visual symptoms increase in incidence with increasing total dose or therapy duration and generally disappear within a few days or weeks after clomiPHENE citrate therapy is discontinued. However, prolonged visual disturbances have been reported after clomiPHENE citrate therapy has been discontinued and these disturbances may be irreversible. 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. These 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 clomiPHENE 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 clomiPHENE citrate administration, which disappeared by the 32nd day after stopping therapy. Postmarketing surveillance of adverse events has also revealed other visual signs and symptoms during clomiPHENE citrate therapy (see ADVERSE REACTIONS). While the etiology of these visual symptoms is not yet understood, patients with any visual symptoms should discontinue treatment and have a completeophthalmological evaluation carried out promptly.




ADVERSE REACTIONS


Clinical Trial Adverse Events

ClomiPHENE citrate, at recommended dosages, is generally well tolerated. Adverse reactions usually have been mild and transient and most have disappeared promptly after treatment has been discontinued. Adverse experiences reported in patients treated with clomiPHENE citrate during clinical studies are


Incidence of Adverse Events in Clinical Studies (Events Greater than 1%) (n = 8029*)


Adverse Event %
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
Blurred vision, lights, floaters, waves, unspecified visual complaints, photophobia, diplopia, scotomata, phosphenes
Headache 1.3
Abnormal Uterine Bleeding 1.3
Intermenstrual spotting, menorrhagia

Includes 498 patients whose reports may have been duplicated in the event totals and could not be distinguished as such. Also, excludes 47 patients who did not report symptom data. The following adverse events have been reported in fewer than 1% of patients in clinical trials: Acute abdomen, appetite increase, constipation, dermatitis or rash, depression, diarrhea, dizziness, fatigue, hair loss/dry hair, increased urinary frequency/volume, insomnia, light-headedness, nervous tension, vaginal dryness, vertigo, weight gain/loss. Patients on prolonged clomiPHENE citrate therapy may show elevated serum levels of desmosterol. This is most likely due to a direct interference with cholesterol synthesis. However, the serum sterols in patients receiving the recommended dose of clomiPHENE citrate are not significantly altered. Ovarian cancer has been infrequently reported in patients who have received fertility drugs. Infertility is a primary risk factor for ovarian cancer; however, epidemiology data suggest that prolonged use of clomiPHENE may increase the risk of a borderline or invasive ovarian tumor.

Dermatologic: Acne, allergic reaction, erythema, erythema multiforme, erythema nodosum, hypertrichosis, pruritus, urticaria.

Central Nervous System: Migraine headache, paresthesia, seizure, stroke, syncope.

Psychiatric: Anxiety, irritability, mood changes, psychosis.

Visual Disorders: Abnormal accommodation, cataract, eye pain, macular edema, optic neuritis, photopsia, posterior vitreous detachment, retinal hemorrhage, retinal thrombosis, retinal vascular spasm, temporary loss of vision.

Cardiovascular: Arrhythmia, chest pain, edema, hypertension, palpitation, phlebitis, pulmonary embolism, shortness of breath, tachycardia, thrombophlebitis.

Musculoskeletal: Arthralgia, back pain, myalgia.

Hepatic: Transaminases increased, hepatitis.

Neoplasms: Liver (hepatic hemangiosarcoma, liver cell adenoma, hepatocellular carcinoma); breast (fibrocystic disease, breast carcinoma); endometrium (endometrial carcinoma); nervous system (astrocytoma, pituitary tumor, prolactinoma, neurofibromatosis, glioblastoma multiforme, brain abscess); ovary (luteoma of pregnancy, dermoid cyst of the ovary, ovarian carcinoma); trophoblastic (hydatiform mole, choriocarcinoma); miscellaneous (melanoma, myeloma, perianal cysts, renal cell carcinoma, Hodgkin’s lymphoma, tongue carcinoma, bladder carcinoma): and neoplasms of offspring (neuroectodermal tumor, thyroid tumor, hepatoblastoma, lymphocytic leukemia).

Genitourinary: Endometriosis, ovarian cyst (ovarian enlargement or cysts could, as such, be complicated by adnexal torsion), ovarian hemorrhage, tubal pregnancy, uterine hemorrhage.

Body as a Whole: Fever, tinnitus, weakness.

Other: Leukocytosis, thyroid disorder.

DRUG ABUSE AND DEPENDENCE: Tolerance, abuse, or dependence with clomiPHENE citrate has not been reported.

OVERDOSAGE Signs and Symptoms: Toxic effects accompanying acute overdosage of clomiPHENE citrate have not been reported. Signs and symptoms of overdosage as a result of the use of more than the recommended dose during clomiPHENE citrate therapy include nausea, vomiting, vasomotor flushes, visual blurring, spots or flashes, scotomata, ovarian enlargement with pelvic or abdominal pain.

Oral LD50:The acute oral LD50 of clomiPHENE citrate is 1700 mg/kg in mice and 5750 mg/kg in rats. The toxic dose in humans is not known.

Dialysis: It is not known if clomiPHENE citrate is dialyzable.