Treatment of sterility due to anovulation and ovulatory dysfunction of higher functional origin with normal blood prolactin:

•        sterility due to anovulation

•        sterility due to ovulatory dysfunction:

o “corpus luteum insufficiency”

o short luteal phase

o polycystic ovarian syndrome.

 

Test for both diagnostic and therapeutic purposes:

•        in some amenorrhoeas of hypothalamic-pituitary origin

•        in long-term amenorrhoea following oral contraception (after having checked that the plasma prolactin level is normal).

Ovulation induction as part of assisted fertilisation (intrauterine insemination, IVF)

Posology

Treatment of sterility due to anovulation and ovulatory dysfunction of higher functional origin with norm al blood prolactin.

The initial dosage is one tablet daily (i.e., 50 mg) for 5 days.

Treatment may begin 2 to 5 days after the start of a natural or progestin-induced withdrawal bleed or, in the absence of a cycle, on a day arbitrarily chosen by the treating physician.

If ovulation occurs, increasing the dosage in subsequent cycles is of no benefit. In the opposite case, (no change in basal temperature, plasma progesterone in days 20 to 26 of the cycle <3 ng/ml), 100 mg may be prescribed daily for 5 days during the second treatment cycle (2 tablets as a single daily dose).

Increasing the daily dose and the duration of treatment to more than 100 mg daily for 5 days is not recommended. If three courses at this dosage have not produced ovulation, the therapeutic trial is considered to be over. If ovulation has been obtained at a dose of 50 or 100 mg without this resulting in a pregnancy, the treatment may be continued for up to a maximum total of six cycles. The efficacy and safety of clomiphene have not been demonstrated for more than 6 cycles of treatment.

Some patients with polycystic ovaries may be hypersensitive to CLOMID, even at the initial dosage (50 mg/day). In this case, the dosage for subsequent cycles may be decreased to half a tablet daily (25 mg/day).

It is important to remind couples of the need for regular sexual intercourse during the presumed fertile period.

CLOMID is not indicated in women who are ovulating. Test for both diagnostic and therapeutic purposes

This test is used to diagnose gonadotropin insufficiency if the patient wishes to become pregnant. The dosage is 2 tablets daily (i.e., 100 mg) for 5 consecutive days and for a single cycle.

Ovulation induction as part of assisted fertilisation (IVF etc.).

Some ovarian stimulation protocols use CLOMID (2 tablets daily from day 2 to 6 of the cycle) followed by hMG for several days leading to the maturation of several follicles.

Method of administration

CLOMID is administered orally and may only be used under specialised medical supervision.

• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. • Severe or recent liver disorders. • Gynaecological haemorrhages of unspecified aetiology. • “Hormone-dependent” neoplasms. • Organic ovarian cysts. • History of significant, medically confirmed, vision disorders related to the use of CLOMID (prior or ongoing treatment) (see section 4.4).

Warnings:

Before administering CLOMID:

•        ensure that the woman is not pregnant before administering CLOMID. If in doubt, perform a sensitive, reliable pregnancy test (review the patient again before each course),

•         ensure that the cause of the sterility is not due to:

o   primary ovarian failure,

o   hypothalamic-pituitary insufficiency of organic origin,

•        investigate for other possible causes of male and female sterility and treat appropriately, if possible,

•        the couple must be warned of the higher probability of a multiple pregnancy and of its potential complications.

•        some studies published in the literature have reported that medicinal products used in the treatment of sterility might increase the risk of onset of some benign or malignant neoplasms, especially hormone-dependent neoplasms. However, it is not possible to draw definite conclusions from the data in the literature about whether or not there is an increased risk of developing certain neoplasms, especially hormone-dependent neoplasms, in patients treated with ovulation inducers.

During treatment:

•        CLOMID, alone or in combination with gonadotrophins, may lead to ovarian hyperstimulation. This is usually moderate but may exceptionally be severe. Rare cases of severe ovarian hyperstimulation syndromes have been reported with the appearance of the following symptoms: pericardial effusion, anasarca, hydrothorax, acute abdomen, renal failure, pulmonary oedema, ovarian haemorrhage, deep vein thrombosis, ovarian torsion and acute respiratory distress. If a woman with ovarian hyperstimulation syndrome becomes pregnant, it may rapidly progress to a severe form of the syndrome.

•        Ovarian hyperstimulation appears a few days after the end of CLOMID treatment.

•        Special care should be taken when the patient complains of pelvic pain, increased weight and a feeling of generalised swelling during treatment. Ultrasound should be used to look for an increase in the volume of the ovaries. A new course of CLOMID therapy should only commence after the ovarian volume returns to normal. The treatment dosage should then be reduced.

Ovarian hyperstimulation with CLOMID only leads to complications in very rare cases.

Visual symptoms:

Patients should be informed that vision disorders such as accommodation disorders, filmy vision, spots or flashes of light (scintillating scotoma), can sometimes occur during or shortly after treatment with CLOMID. These vision disorders are generally reversible; however, cases of prolonged or irreversible vision disorders sometimes associated with partial or complete visual impairment (blindness) have been reported including after the discontinuation of CLOMID.

These vision disorders especially occur when the dosage or duration of treatment is increased (see sections 4.7 and 4.8).

The patient should be advised to stop treatment immediately if any unusual visual symptoms appear and to inform the doctor. In such cases, a complete ophthalmological examination is necessary and the treatment should be permanently discontinued if no other cause of vision disorder has been determined.

A few rare cases of posterior capsular cataracts have been reported in patients taking CLOMID, though a cause-and-effect relationship has been neither established nor ruled out.

Hypersensitivity reactions

Hypersensitivity reactions including anaphylaxis and angio-oedema have been reported when CLOMID is used. If allergic reactions occur, CLOMID treatment should be discontinued and appropriate symptomatic treatment should be initiated (see section 4.8).

Precautions for use

•        In obese patients, appropriate dietary measures are recommended throughout treatment, in order to obtain a significant weight loss. As with any ovulation-inducing treatment, the start of treatment must be postponed in significant obesity and dietary measures considered as a priority.

•        CLOMID must only be used under specialised medical supervision.

•        The patient must be monitored clinically (functional signs, basal body temperature) and possibly biologically, with a plasma progesterone assay performed between day 20 and 26 of the cycle.

•        During a cycle induced by CLOMID, any possible progestin treatment must not be prescribed before day 20 of the cycle so as not to alter the cervical mucus, especially when ovulation is a little delayed. At the end of an anovulatory cycle, the use of a course of progestin to obtain a withdrawal bleed allows a new therapeutic course to be considered at a higher dosage without delay.

•        Special monitoring is recommended in patients with a uterine fibroid because of the risk of hypertrophy of the fibroid.

•        Although isolated cases of congenital anomalies have been observed after CLOMID treatment, CLOMID has not been shown to modify the frequency of birth defects in children born to women with fertility problems. Maternal age and multiple pregnancies are risk factors for foetal or neonatal abnormalities.

•        Cervical mucus insufficiency due to the antioestrogenic action of CLOMID may warrant associated local oestrogen therapy.

•        Cases of hypertriglyceridaemia have been reported (see section 4.8, Undesirable effects). Preexisting or familial hypertriglyceridaemia, and use at higher doses and/or for longer durations of treatment than recommended, are associated with a risk of hypertriglyceridaemia. Regular monitoring of the plasma triglyceride level may be indicated in these patients.

•        CLOMID may interfere with the synthesis of cholesterol when it is administered for long periods of time. Patients who have prolonged treatment may have high levels of desmosterol.

•        This medicinal product contains sucrose. Its use is not recommended in patients with fructose intolerance, glucose-galactose malabsorption syndrome or sucrase-isomaltase deficiency.

•        This medicinal product contains lactose. Its use is not recommended in patients with galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome (rare hereditary illnesses).

No drug interactions have been described with clomiphene.

Animal studies have shown a teratogenic effect.

There are currently insufficient relevant clinical data to assess whether this medicinal product has any malformative or foetotoxic effect when it is administered during pregnancy.

There is no indication for this medicinal product during pregnancy. However, in the event of accidental exposure, there is no argument for recommending termination of pregnancy.

CLOMID has moderate influence on the ability to drive and use machines. Patients should be warned that filmy vision or other visual symptoms may occasionally occur during treatment with CLOMID or immediately after its discontinuation. These visual symptoms can make activities such as driving a car or using machines more dangerous than usual, particularly under variable lighting conditions (see section 4.4).

Reproductive system and breast disorders:

•        ovarian hyperstimulation (see section 4.4).

•        cervical mucus insufficiency due to the antioestrogenic action of CLOMID which may warrant associated local oestrogen therapy.

A few cases of endometriosis or the worsening of pre-existing endometriosis have been reported.

•        hypermenorrhoea, breakthrough bleeding

•        breast tenderness

•        pelvic discomfort

•        reduced endometrial thickness

Renal and urinary disorders:

•        pollakiuria

Pregnancy, puerperium and perinatal conditions:

•        moderate risk of multiple pregnancy including simultaneous intrauterine and ectopic pregnancies: the risk of an ectopic pregnancy is increased after a course of CLOMID.

Eye disorders:

Common

Scintillating scotoma (spots or flashes).

Rare

Optic neuritis

Not known

•        Reduced visual acuity;

•        Diplopia;

•        Ocular pain;

•        Accommodation disorders;

•        Optic ischaemic neuropathy;

•        Retinal detachment;

•        Central retinal vein occlusion;

•        Vitreous detachment;

Since marketing, the above-mentioned undesirable effects have been reported, in some cases associated with reversible or irreversible, partial or total visual impairment (blindness), in particular with an increase in the dosage or duration of treatment (see sections 4.3, 4.4 and 4.9).

Cardiac disorders:

•        Tachycardia, palpitations;

Skin and subcutaneous tissue disorders:

•        urticaria or allergic dermatitis, alopecia

Neoplasms benign, malignant and unspecified :

Isolated cases of the onset or worsening of some neoplasms, usually hormone-dependent neoplasms, have been reported.

Nervous system disorders:

•        Headaches, vertigo, light-headedness and feeling of drunkenness, transient paraesthesia.

•        Cases of convulsions have been reported.

Psychiatric disorders:

•        a few cases of worsening of pre-existing psychosis have been reported,

•        the following have also been reported: anxiety, depression, mood disorders (including changes in mood, mood swings and irritability), nervousness, insomnia.

Vascular disorders:

•        hot flushes.

Hepatobiliary disorders:

•        increased transaminases.

Gastrointestinal disorders:

•        nausea, vomiting,

•        abdominal discomfort (distension, bloating),  pancreatitis.

Metabolism disorders:

Hypertriglyceridaemia sometimes associated with pancreatitis has been observed in patients with preexisting or familial hypertriglyceridaemia and/or when used at a dose and for a duration greater than those recommended. Regular monitoring of the plasma triglyceride level may be indicated in these patients.

Immune system disorders:

Hypersensitivity reactions, including anaphylaxis and angio-oedema (Frequency not known).

Reporting of suspected adverse reactions

To report any side effect(s):

·       Saudi Arabia:

-        The National Pharmacovigilance and Drug Safety Centre (NPC)

·       SFDA call center : 19999

·       E-mail: npc.drug@sfda.gov.sa

·       Website: https://ade.sfda.gov.sa/

Sanofi-Pharmacovigilance: KSA_Pharmacovigilance@sanofi.com

No cases of acute poisoning have been reported.

In the event of an overdose, nausea, vomiting, hot flushes, potentially irreversible vision disorders, ovarian enlargement with abdominal and pelvic pain may be observed.

Pharmacotherapeutic group: ovulation stimulants, ATC code: G03GB02.

Competitively inhibits the negative feedback of oestrogens in the hypothalamus, thus leading to an increase in FSH causing follicular maturation. Follicular maturation is accompanied by an increase in oestradiol secretion, which promotes the onset of a LH peak and triggers ovulation and the formation of a secreting corpus luteum.

In 5,413 patients with ovulation disorders, CLOMID treatment produced ovulation in more than 70% of cases.

After oral administration, the product is well absorbed; its elimination is mainly faecal, the product and its metabolites being slowly eliminated via enterohepatic recycling.

Reproductive toxicity

Clomiphene was shown to have a harmful effect (inhibition of foetal development and possible foetal abnormalities) in rat and rabbit foetuses when high doses were administered to pregnant animals.

Carcinogenicity — Mutagenicity

Long-term carcinogenicity studies have not been conducted to assess the carcinogenic potential of CLOMID.

Clomiphene citrate did not induce any gene mutations in bacteria (Ames test) nor any chromosomal aberrations in cultures of lymphocytes from human peripheral blood. Clomiphene citrate administered at oral doses of up to 2,000 mg/kg/day did not induce a genotoxic effect in rats.

At the highest dose tested in rats, 2,000 mg/kg/day, the exposure ratios ranged from 2 to 232 for Z-clomiphene and E-clomiphene respectively, taking into account the limited pharmacokinetic data available in human subjects.

Sucrose, lactose monohydrate, maize starch, soluble starch, magnesium stearate and yellow iron oxide (E172).

Not applicable.

3 years.

Store below 30°C. Protect from light, moisture and excessive heat.

5 or 10 tablets in PVC/aluminium blisters

Not applicable.