Clomifene Other names: Chlomaphene Chloramifene Chloramiphene Cisclomiphene Zuclomiphene

Ovarian Hyperstimulation Syndrome (OHSS) has been reported in patients receiving clomifene for ovulation induction. In some cases, OHSS occurred following the cyclic use of clomifene or when clomifene was used in combination with gonadotropins. The following symptoms have been reported in association with this syndrome during clomifene: 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 clomifene, the lowest dose consistent with expectation of good resultclomifenelvic pain, weight gain, discomfort or distension after taking clomifene. Maximal enlargement of the ovary may not occur until several days after discontinuation of the course of clomifene. Some patients with polycystic ovary syndrome who are unusually sensitive to gonadotropin may have an exaggerated response to usual doses of clomifene.

The patient who complains of abdominal or pelvic pain, discomfort, or distension after taking clomifene 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 clomifene should not be given until the ovaries have returned to pre-treatment size. Ovarian enlargement and cyst formation associated with clomifene 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 clomifene. These visual disturbances are usually reversible; however, cases of prolonged visual disturbance have been reported including after clomifene 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.

There is an increased chance of multiple pregnancy when conception occurs in relationship to clomifene 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 clomifene 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.

Cases of hypertriglyceridemia have been reported in the post-marketing experience with clomifene. Pre-existing or family history of hyperlipidemia and use of higher than recommended dose and/or longer duration of treatment with clomifene are associated with risk of hypertriglyceridemia. Periodic monitoring of plasma triglycerides may be indicated in these patients.

There is an increased chance of ectopic pregnancy (including tubal and ovarian sites) in women who conceive following clomifene therapy. Multiple pregnancies, including simultaneous intrauterine and extrauterine pregnancies, have been reported.

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 clomifene may increase this risk. Therefore the recommended duration of treatment should not be exceeded.

Caution should be exercised when using clomifene in patients with uterine fibroids due to potential for further enlargement of the fibroids.

Clomifene is not indicated during pregnancy. Although there is no evidence that clomifene has a harmful effect on the human foetus, there is evidence that clomifene has a deleterious effect on rat and rabbit foetuses when given in high doses to the pregnant animal. To avoid inadvertent clomifene administration during early pregnancy, appropriate tests should be utilised during each treatment cycle to determine whether ovulation occurs. The patient should have a pregnancy test before the next course of clomifene therapy.

It is not known whether clomifene citrate is excreted in human milk. Clomifene may reduce lactation.

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.

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 clomifene therapy consisted of 100mg daily for 14 days. Abnormal ovarian enlargement usually regresses spontaneously; most of the patients with this condition should be treated conservatively.

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 clomifene 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 clomifene 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 clomifene 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. Ovarian cancer.

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/insonmia (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).

Dermatoses: 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, erythema multiforme, 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 clomifene now recommended. Retention was usually minimal unless associated with prolonged continuous clomifene 50 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 clomifene (50 or 100mg 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 placebo.

In a separate report, one patient taking 50mg of clomifene 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 pre-existing 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)