OVA-MIT Tablet Ref.[28218] Active ingredients: Clomifene

Warnings

The purpose and risks of Ova-mit therapy should be presented to the patient before starting treatment. It should be emphasized that the goal of Ova-mit 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 clomifene citrate therapy for ovulation induction. In some cases, OHSS occurred following the cyclic use of clomifene citrate therapy or when clomifene citrate was used in combination with gonadotropins. Rare cases of severe forms of OHSS have been reported where the following symptoms have occurredduring clomifene citrate 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 clomifene citrate 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 Ova-mit. Maximal enlargement of the ovary may not occur until several days after discontinuation of the course of Ova-mit. Some patients with polycystic ovary syndrome who are unusually sensitive to gonadotropin may have an exaggerated response to usual doses of Ova-mit.

The patient who complains of abdominal or pelvic pain, discomfort, or distension after taking Ova-mit 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 Ova-mit should not be given until the ovaries have returned to pre-treatment size. Ovarian enlargement and cyst formation associated with Ova-mit 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 Ova-mit.

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 clomifene citrate tablet discontinuation. The visual disturbances 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 ophthalmologic evaluation performed.

Precautions

Cases of hypertriglyceridemia have been reported (see section 4.8 Undesirable effects) in the post-marketing experience with clomifene citrate tablets. Pre-existing or family history of hyperlipidemia and use of higher than recommended dose and/or longer duration of treatment with Ova-mit are associated with risk of hypertriglyceridemia. Periodic monitoring of plasma triglycerides may be indicated in these patients.

Treatment with Ova-mit 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 Ova-mit therapy. During the clinical investigation studies, the incidence of multiple pregnancy was 7.9% (186 of 2369 clomifene citrate 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 Ova-mit therapy. Ectopic pregnancy associated with clomifene citrate involves a multiple pregnancy with coexisting extrauterine and intrauterine gestations.

Uterine Fibroids

Caution should be exercised when using Ova-mit 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 clomifene citrate 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 clomifene citrate, 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 Ova-mit 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 Ova-mit 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 clomifene citrate 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 clomifene citrate shows a pregnancy (single and multiple) wastage 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%.

Clomifene citrate 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 clomifene citrate 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.

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.

None stated.

Pregnancy

Ova-mit is not indicated during pregnancy. See contraindications (See section 4.3, Contraindications).

Lactation

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. (See section 4.4, Special warnings and precautions for use).

The following CIOMS frequency rating is used, when applicable: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to ≤ 1/100); rare (≥1/10,000 to ≤1/1,000); very rare (≥1/10,000); not known (cannot be estimated from the available data).

Symptoms/Signs/Conditions

Adverse effects appeared to be dose- related, occurring more frequently at the higher dose and with a longer courses of treatment used in investigational studies. At recommended dosage, adverse effects are not prominent and infrequently interfere with treatment.

Reproductive system and breast disorders

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 citrate 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.

Eye disorders

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. These are rare reports of cataracts and optic neuritis.

These visual disturbances are usually reversible. However, cases of prolonged visual disturbances have been reported, including after clomifene citrate discontinuation. The visual disturbances may be irreversible, especially with increased dosage or duration of therapy (See section 5).

Tumours/neoplasms

Isolated reports have been received on the occurrence of endocrine-related or dependent neoplasms of their aggravation. Ovarian cancer: see section 4.4.

Central nervous system

Convulsions have been reported; patients with a history of seizures may be predisposed. 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 disturbances.

Hepatobiliary disorders

Increased transaminases have been reported.

The Bromsulphalein test (BSP) is a test of liver function based on the removal of a known quantity of Brom-sulphalein from the blood in a measured period of time. Normal values are less than 5% retention at the end of 45 minutes with an intravenous dose of 5 mg/kg body weight. It is a useful test of hepatocellular disease and detoxifying ability but is not applicable in the presence of extra-hepatic or intrahepatic obstructive jaundice.

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 citrate tablets now recommended. Retention was usually minimal unless associated with prolonged continuous clomifene citrate 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 citrate tablets (50 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 placebo.

In a separate report, one patient taking 50 mg clomifene citrate tablets daily developed jaundice on the 19th day of treatment; liver biopsy revealed bile stasis without evidence of hepatitis.

Metabolism Disorders

Hypertriglyceridemia 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continue monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: Cyprus, Pharmaceutical Services, Ministry of Health, CY-1475 Nicosia, Tel: +357 22608607, Fax: +357 22608669, Website: www.moh.gov.cy/phs.

Not applicable.