Source: Υπουργείο Υγείας (CY) Revision Year: 2015 Publisher: MEDOCHEMIE LTD, 1-10 Constantinoupoleos street, 3011 Limassol, Cyprus
Good levels of endogenous oestrogen (as estimated from vaginal smears, endometrial biopsy, assay of urinary oestrogen, or endometrial bleeding in response to progesterone) provide a favourable prognosis for ovulatory response induced by Duinum . A low level of oestrogen, although clinically less favourable, does not preclude successful outcome of therapy. Duinum therapy is ineffective in patients with primary pituitary or primary ovarian failure. Duinum therapy cannot be expected to substitute for specific treatment of other causes of ovulatory failure, such as thyroid or adrenal disorders. For hyperprolactinaemia there is other preferred specific treatment. Duinum is not first line treatment for low weight related amenorrhoea, with infertility, and has no value if a high FSH blood level is observed following an early menopause.
Ovarian Hyperstimulation Syndrome (OHSS) has been reported in patients receiving Duinum therapy for ovulation induction. In some cases, OHSS occurred following the cyclic use of Duinum therapy or when Duinum was used in combination with gonadotropins. The following symptoms have been reported in association with this syndrome during Duinum 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 Duinum 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 Duinum. Maximal enlargement of the ovary may not occur until several days after discontinuation of the course of Duinum. Some patients with polycystic ovary syndrome who are unusually sensitive to gonadotropin may have an exaggerated response to usual doses of Duinum.
The patient who complains of abdominal or pelvic pain, discomfort, or distension after taking Duinum 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 Duinum should not be given until the ovaries have returned to pre-treatment size. Ovarian enlargement and cyst formation associated with Duinum therapy usually regresses 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.
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 Duinum. 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.
Cases of hypertriglyceridemia have been reported (see section 4.8) 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 Duinum are associated with risk of hypertriglyceridemia. Periodic monitoring of plasma triglycerides may be indicated in these patients.
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.
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.
Caution should be exercised when using Duinum in patients with uterine fibroids due to potential for further enlargement of the fibroids.
The overall incidence of reported birth anomalies from pregnancies associated with maternal Duinum 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 Duinum, 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 Duinum 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 Duinum 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 Duinum 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 Duinum 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%.
Duinum 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 Duinum 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.
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 Duinum may increase this risk. Therefore the recommended duration of treatment should not be exceeded (see section 4.2).
Duinum contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.
None stated.
Clomifene is not indicated during pregnancy. Although there is no evidence that Duinum has a harmful effect on the human foetus, there is evidence that Duinum 50mg Tablets has a deleterious effect on rat and rabbit foetuses when given in high doses to the pregnant animal. To avoid inadvertent Duinum 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 Duinum 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 (see section 4.4).
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 common reported adverse effects included ovarian enlargement (13.6%), vasomotor flushes (10.4%), abdominal-pelvic discomfort (distension, 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%).
Tumours/neoplasms: Isolated reports have been received on the occurrence of endocrine-related or dependent neoplasms or their aggravation. Ovarian cancer: See section 4.4.
At recommended dosage, abnormal ovarian enlargement is infrequent although the usual cyclic variation in ovarian size may be exaggerated. Similarly, cyclic ovarian pain 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 Duinum 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.
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.
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 disturbance.
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 Duinum have been discontinued. The visual disturbances may be irreversible, especially with increased dosage or duration of therapy.
Tachycardia, (frequency not known) palpitations (frequency not known)
Pancreatitis (frequency not known)
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 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.
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.
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)
Reporting suspected adverse reactions is an important way to gather more information to continuously monitor the benefit/risk balance of the medicinal product. Any suspected adverse reactions should be reported to Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy/phs, Fax: +357 22608649.
Not applicable.
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