SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Clomifene Citrate Tablets BP 50mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 50mg Clomifene Citrate BP For excipients, see 6.1 3. PHARMACEUTICAL FORM Tablet

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Clomifene citrate tablets are indicated for the treatment of ovulatory failure in women with hypothalamic-pituitary dysfunction (including polycystic ovarian syndrome). Other causes of infertility must be excluded or adequately treated before giving Clomifene citrate tablets.

4.2    Posology and method of administration

Route of Administration:

Oral.

Adults Only :

The recommended dose for the first course of Clomifene citrate 50mg Tablets is 50mg (1 tablet) daily for 5 days. Therapy may be started at any time in the patient who has had no recent uterine bleeding. If progestin-induced bleeding is planned, or if spontaneous uterine bleeding occurs before therapy, the regimen of 50mg daily for 5 days should be started on or about the fifth day of the cycle. When ovulation occurs at this dosage, there is no advantage to increasing the dose in subsequent cycles of treatment.

If ovulation appears not to have occurred after the first course of therapy, a second course of 100mg daily (two 50mg tablets given as a single daily dose) for 5days should be given. This course may be started as early as 30 days after the previous one. Increase of the dosage or duration of therapy beyond 100mg/day for 5 days should not be undertaken.

The majority of patients who are going to respond will respond to the first course of therapy, and 3 courses should constitute an adequate therapeutic trial. If ovulatory menses have not yet occurred, the diagnosis should be reevaluated. Treatment beyond this is not recommended in the patient who does not exhibit evidence of ovulation.

Long-term Cyclic Therapy:

Not recommended.

The relative safety of long-term cyclic therapy has not been conclusively demonstrated and, since the majority of patients will ovulate following 3 courses, long-term cyclic therapy is not recommended, i.e. beyond a total of about 6 cycles (including 3 ovulatory cycles).

4.3    Contraindications

Liver Disease : Clomifene citrate therapy is contraindicated in patients with liver disease or a history of liver dysfunction.

Abnormal Uterine Bleeding : Clomifene citrate is contraindicated in patients with abnormal bleeding of undetermined origin.

Ovarian Cyst: (except polycystic ovarian syndrome) ; ovarian endometriosis. See 'precautions'.

Pregnancy : Clomifene citrate is contraindicated in pregnant and lactating women. See 'use in pregnancy and lactation'.

4.4    Special warnings and precautions for use Warnings:

General: 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 Clomifene citrate tablets. A low level of oestrogen, although clinically less favourable, does not preclude successful outcome of therapy.

Clomifene citrate tablets therapy is ineffective in patients with primary pituitary or primary ovarian failure. Clomifene citrate tablets 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 no other preferred treatment.

Clomifene citrate tablets 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 Hyper stimulation Syndrome: Ovarian Hyperstimulation Syndrome (OHSS) has been reported in patients receiving Clomifene citrate tablets therapy for ovulation induction. In some cases, OHSS occurred following the cyclic use of Clomifene citrate tablets therapy or when Clomifene citrate tablets was used in combination with gonadotropins. The following symptoms have been reported in association with this syndrome during Clomifene citrate tablets 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 tablets 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 Clomifene citrate tablets. Maximal enlargement of the ovary may not occur until several days after discontinuation of the course of Clomifene citrate tablets. Some patients with polycystic ovary syndrome who are unusually sensitive to gonadotropin may have an exaggerated response to usual doses of Clomifene citrate tablets.

The patient who complains of abdominal or pelvic pain, discomfort or distension after taking Clomifene citrate tablets should be examined because of 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 citrate tablets should not be given until the ovaries have returned to pre-treatment size. Ovarian enlargement and cyst formation associated with Clomifene citrate tablets 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 may occasionally occur during or shortly after therapy with Clomifene citrate tablets. 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:

Multiple Pregnancy. There is an increased chance of multiple pregnancy when conception occurs in relationship to Clomifene citrate therapy. During the clinical investigation studies, the incidence of multiple pregnancy was 7.9% (186 of 2469 associated pregnancies on which outcome was reported). Among these 2369 pregnancies, 2183 (92.1%) were single, 165 (6.9%) twin, 11 (0.5%) triplet, 7 (0.3%) quadruplet and 3 (0.13%) quintuplet.

Ectopic Pregnancy: There is an increased chance of ectopic pregnancy (including tubal and ovarian sites) in women who conceive following Clomifene citrate tablets therapy. Ectopic pregnancy associated with Clomifene citrate tablets involves a multiple pregnancy with coexisting extrauterine and intrauterine gestations.

Uterine Fibroids: Caution should be exercised when using Clomifene citrate tablets 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 tablets ingestion (before or after conception) during the investigational studies was within the range of that reported in 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 tablets, 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 Clomifene citrate Tablets or occurred naturally.

The patient should be informed of the greater pregnancy risks associated with certain characteristics or conditions of any pregnant women : 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 it 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 spontaneous aborted foetuses from subfertile women receiving ovulation inducing drugs (no women with Clomifene citrate tablets alone and without additional inducing drugs). 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.

Ovarian Cancer: 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 citrate tablets may increase this risk.

Therefore the recommended duration of treatment should not be exceeded (see 'Posology and Method of Administration').

Patients with rare hereditary problems of galactose or fructose intolerance, the Lapp lactase deficiency, sucrase-isomaltase insufficiency or glucose-galactose malabsorption should not take this medicine.

4.5    Interaction with other medicinal products and other forms of interaction

None known

4.6    Pregnancy and lactation

Clomifene citrate tablets are contraindicated during pregnancy and breast feeding.

Clomifene citrate tablets is contraindicated during pregnancy. Although there is no evidence that Clomifene citrate tablets has a harmful effect on the human foetus, there is evidence that Clomifene citrate has a deleterious effect on rat and rabbit foetuses when given in high doses to the pregnant animal. To avoid inadvertent Clomifene tablets 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 citrate tablets therapy.

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

4.7    Effects on ability to drive and use machines

Patients should be warned that visual symptoms may render activities such as driving a car or operating machinery more hazardous than usual, particularly under conditions of variable lighting. If the patient has any visual symptoms, treatment should be discontinued and ophthalmological evaluation performed.

4.8    Undesirable effects

Symptoms / Signs / Conditions : Adverse effects appeared to be dose related, occurring more frequently at higher doses and with longer courses of treatment used in investigational studies. At recommended dosage, adverse effects are not prominent and infrequently interfere with treatment.

During investigational studies, the more common reported adverse effects included ovarian enlargement (13.6 %), vasomotor flushes (10.4 %), abdominal-pelvic discomfort (distension, bloating) (5.5 %). The vasomotor symptoms resembling menopausal 'hot flushes' were rarely severe and disappeared promptly after treatment was discontinued. Abdominal symptoms were most often related to ovulatory or premenstrual phenomena, or to ovarian enlargement.

Tumours / Neoplasms: Isolated reports have been received on the occurrence of endocrine-related or dependent neoplasms or their aggravation. Ovarian cancer: see 'Special Warnings and Special Precautions for Use'.

CNS Symptoms: 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 such conditions as syncope/fainting, cerebrovascular accident, cerebral thrombosis, psychotic reactions including paranoid psychosis, neurologic impairment, disorientation and speech disturbance.

Convulsions have been reported. Patients with a history of seizures may be predisposed.

Eye / Visual Symptoms: Symptoms described usually as 'blurring' or spots or flashes (scintillating scotomata). Increase in incidence with increasing total dose usually disappear within periods ranging from a few days to a few weeks after Clomifene citrate tablets is discontinued.

Opthalmologically definable scotomata and retinal cell function (electroretinographic) changes have been reported.

There are rare reports of cataracts. Other conditions of which there were isolated reports include conditions such as: optic neuritis, retinal haemorrhage/thrombosis/vascular spasm, temporary loss of vision, macular oedema.

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 citrate now recommended. Retention time was usually minimal unless associated with prolonged continuous Clomifene citrate administration or with apparently unrelated liver disease. Other liver function tests were usually normal.

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 has been reported very rarely.

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 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. Abnormal ovarian enlargement usually regresses spontaneously. Most of the patients with this condition should be treated conservatively.

Ovarian Cancer : 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 (see dosage and administration).

Genitourinary Effects: There are reports of new cases of endometriosis and exacerbation of pre-existing endometriosis during Clomifene citrate tablets therapy.

Multiple pregnancies, including simultaneous intrauterine and extrauterine pregnancies, have been reported.

4.9 Overdose

There is no experience of acute poisoning with Clomifene citrate.

Hyperstimulation may occasionally result from an excessive response to Clomifene citrate therapy. Hyperstimulation is categorised as mild, moderate or severe. Generally, hyperstimulation will be mild or very rarely, moderate, after Clomifene citrate treatment. Symptoms usually appear 3-6 days after ovulation or chorionic gonadotrophin.

Mild hyperstimulation - symptoms may include some abdominal swelling and pain; ovaries enlarged to 5cm diameter. Therapy - rest, careful observation and symptomatic relief. Ovarian enlargement declines rapidly.

Moderate hyperstimulation - symptoms include more pronounced abdominal distension and pain, nausea, vomiting, occasional diarrhoea; ovaries enlarged up to 12cm diameter. Therapy - bed rest; close observation in case of conception occurring, to detect any progression to severe hyperstimulation. Pelvic examination should be gentle in order to avoid rupture of the cysts. Symptoms subside spontaneously over 2-3 weeks.

Severe hyperstimulation - a rare but serious complication - symptoms include pronounced abdominal distension and pain, ascites, pleural effusion, decreased blood volume, reduced urine output, electrolyte imbalance and sometimes shock; ovaries enlarged to in excess of 12cm diameter and may contain cysts. Therapy - hospitalisation. Treatment should be conservative, concentrating on restoring the blood volume and preventing shock. Acute symptoms subside over several days and ovaries return to normal after 20-40 days if conception does not occur. Symptoms may be prolonged if conception has occurred.

5 PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group:

Gonadotropins & other ovulation stimulants

ATC code:

G03G B02

Clomifene is chemically related to Chlorotrianisene and has both oestrogenic and anti-oestrogenic properties. It exerts its therapeutic effects by stimulating the secretion of pituitary gonadotrophic hormones, probably by blocking the effect of oestrogens at receptor sites in the hypothalamus and pituitary.

5.2    Pharmacokinetic properties

Clomifene citrate is absorbed from the gastro-intestinal tract. It is metabolised in the liver and slowly excreted via the bile. Unchanged drug and metabolites are excreted in the faeces. The biological half life is reported to be 5 days although traces are found in the faeces for up to 6 weeks. Enterohepatic recirculation takes place.

5.3    Preclinical safety data

There are no preclinical safety data of relevance to the prescriber which are additional to those already included in other sections of the SPC.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose Hydrous 200 BP Maize Starch BP Sucrose BP

Quinoline Yellow Lake Fr.P Sta-Rx 1500 BP Purified Talc BP Magnesium Stearate BP.

6.2    Incompatibilities

None known

6.3    Shelf life

3 years

Special precautions for storage

Protect from light. Store in a cool dry place and at a temperature not exceeding 25°C.

6.5    Nature and contents of container

Blister strips in packs of 30 tablets

6.6    Special precautions for disposal

None

7. MARKETING AUTHORISATION HOLDER

Generics [UK] Ltd Station Close Potters Bar Hertfordshire EN6 1TL

8    MARKETING AUTHORISATION NUMBER(S)

PL 04569/0059

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

16/02/2005

10    DATE OF REVISION OF THE TEXT

16/02/2005